ArticleLiterature Review

Advances in the understanding of mantle cell lymphoma

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Abstract

Mantle cell lymphoma (MCL) is a well-defined lymphoid neoplasm characterized by a proliferation of mature B lymphocytes expressing CD5 that may show a spectrum of morphological and phenotypic features broader than initially described. Although some patients may follow an indolent clinical evolution, in most of them the tumour has an aggressive behaviour with poor response to conventional chemotherapy. The genetic hallmark is the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1, which is considered the initial oncogenic event. In addition to this translocation, MCL may carry a high number of secondary chromosomal and molecular alterations that target regulatory elements of the cell cycle machinery and senescence (BMI1/INK4/ARF/CDK4/RB1), DNA damage response pathways (ATM/CHK2/p53), and cell survival signals. The knowledge of these mechanisms and their influence on the behaviour of the tumour are facilitating the development of prognostic models with a more precise prediction of the clinical evolution of the patients. This information coupled with the availability of a new generation of innovative drugs targeting basic molecular process of the tumour cells, should facilitate the design of new therapeutic protocols able to overcome the resistance of this aggressive lymphoma to conventional treatments and improve the life expectancy of the patients.

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... Furthermore, MCLs are heterogeneous regarding their response to targeted therapy using ibrutinib, an inhibitor of the Bruton tyrosine kinase (BTK), a central mediator of B-cell receptor (BCR) signaling. Likewise, for most NHL including MCL, males are more affected than females with male-to-female incidence ratios for MCL varying between 2 and 7:1 in different reports [2,3]. Furthermore, male sex has, in an observational study, been identified as an independent negative prognostic factor [4]. ...
... The tumor size was measured daily and calculated as 0.5 × length (mm) × width 2 (mm) using a caliper. Mice were sacrificed at the same number of days following the start of treatment except in the case of Granta-519 MCL tumors, where mice were sacrificed when the tumor size of both the DPN-and vehicle-treated mice reached 1300 mm 3 . For a further analysis of the Granta-519 MCL tumors, half of the tumor tissue was fixed in 4% formaldehyde dissolved in PBS for 24 h then transferred to 70% ethanol and stored at 4 • C for TUNEL and Ki67 staining. ...
Article
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Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma with one of the highest male-to-female incidence ratios. The reason for this is not clear, but epidemiological as well as experimental data have suggested a role for estrogens, particularly acting through estrogen receptor β (ESR2). To study the ESR2 effects on MCL progression, MCL cells sensitive and resistant to the Bruton tyrosine kinase inhibitor ibrutinib were grafted to mice and treated with the ESR2-selective agonist diarylpropionitrile (DPN). The results showed that the DPN treatment of mice grafted with both ibrutinib-sensitive and -resistant MCL tumors resulted in impaired tumor progression. To identify the signaling pathways involved in the impaired tumor progression following ESR2 agonist treatment, the transcriptome and ESR2 binding to target genes were investigated by genome-wide chromatin immunoprecipitation in Granta-519 MCL tumors. DPN-regulated genes were enriched in several biological processes that included cell–cell adhesion, endothelial–mesenchymal transition, nuclear factor-kappaB signaling, vasculogenesis, lymphocyte proliferation, and apoptosis. In addition, downregulation of individual genes, such as SOX11 and MALAT1, that play a role in MCL progression was also observed. Furthermore, the data suggested an interplay between the lymphoma cells and the tumor microenvironment in response to the ESR2 agonist. In conclusion, the results clarify the mechanisms by which estrogens, via ESR2, impair MCL tumor progression and provide a possible explanation for the sex-dependent difference in incidence. Furthermore, targeting ESR2 with a selective agonist may be an additional option when considering the treatment of both ibrutinib-sensitive and -resistant MCL tumors.
... It is also possible to simulate alternative rearrangements to better understand the effect of break-point variation between patients. Up to 50% of t(11;14) MCL break-points are within the socalled major translocation cluster (MTC) about 120 kbp upstream of CCND1 [40], with the rest scattered throughout a broader 380 kbp region around this (the Z-138 breakpoint is about 60 kbp upstream of CCND1). Supplementary Figure 4 shows simulated 4C from two different examples where the chromosome 14 break-point is kept the same but we move the break-point on chromosome 11 to different positions: one 11 kbp upstream of CCND1, and one about 100 kbp upstream. ...
Preprint
Genomic rearrangements are known to result in proto-oncogene deregulation in many cancers, but the link to genome 3D structure remains poorly understood. Here we used the highly-predictive heteromorphic polymer (HiP-HoP) model to predict chromatin conformations at the proto-oncogene CCND1 in healthy and malignant B-cells. After confirming that the model gives good predictions of Hi-C data for the non-malignant human B-cell derived cell line GM12878, we generated predictions for two cancer cell lines, U266 and Z-138. These possess genome rearrangements involving CCND1 and the immunoglobulin heavy chain locus (IGH), which we mapped using targeted genome sequencing. Our simulations showed that a rearrangement in U266 cells where a single IGH super-enhancer is inserted next to CCND1 leaves the local topologically associated domain (TAD) structure intact. They also revealed extensive changes in enhancer-promoter interactions within the TAD, and suggested that it is the downstream "epigenetic rearrangement" or chromatin remodelling which gives rise to this, rather than the presence of the inserted super-enhancer per se. Simulations of the IGH-CCND1 reciprocal translocation in Z-138 cells suggested that an oncogenic fusion TAD encompassing CCND1 and the IGH super-enhancers is created. We used the model to predict how the structure of CCND1 changes in these different cell lines, and demonstrated that the simulations can be used to predict differences in chromatin interactions and gene expression for different translocation break-points.
... Although flow cytometry can detect low-level leukemic involvement in many MCL patients at initial diagnosis, there is a distinct entity, the non-nodal leukemic variant (LV-MCL), which is characterized by peripheral blood, bone marrow, and splenic involvement in the absence of high tumor burden lymphadenopathy [1,9,10]. Overall, about 20% of all patients present with this LV-MCL, which is associated with longer survival than cMCL and often may be observed without any lymphoma treatment at initial diagnosis [1,[11][12][13]. ...
Article
Full-text available
Purpose of Review This review summarizes the unique presentation and management of the leukemic variant of mantle cell lymphoma (LV-MCL, also referred to as non-nodal MCL) and highlights the biologic and clinical differentiation from classical mantle cell lymphoma (cMCL) in biomarker expression, clinical features, prognosis, disease course, and treatment. Recent Findings Several studies have evaluated the gene expression profile of mantle cell lymphoma, differentiating LV-MCL from cMCL. The typical immunophenotypic profile is CD5-positive, SOX 11-negative, CD23-low, CD200-low, and cyclin D1 overexpressed. LV-MCL commonly has mutated immunoglobulin heavy chain variable region genes. Data on treatment of LV-MCL is limited to retrospective analyses; the ideal treatment for these patients is unknown although many have a clinically indolent, asymptomatic presentation and often may be observed for an extended period without active treatment. Summary LV-MCL is a clinically and biologically distinct entity. Clinically, it must be distinguished from chronic lymphocytic leukemia and cMCL. Future prospective, randomized clinical trials are required to optimize management, define the initial treatment, and appropriately sequence treatment modalities.
... Mantle cell lymphoma (MCL) is a distinct, highly heterogeneous mature B cell lymphoma characterized by aberrant expression of cyclin D1 (1), which represents about 3-10% of non-Hodgkin's lymphomas (NHL) (2). Most MCL patients are diagnosed at stage III-IV with symptoms including lymphadenopathy, hepatosplenomegaly, bone marrow involvement, and leukemic spread. ...
Article
Full-text available
Mantle cell lymphoma (MCL) is an especially aggressive and highly heterogeneous mature B cell lymphoma. Heat shock protein 90 (HSP90) is considered an attractive therapeutic target in a variety of cancers, including MCL, but no HSP90 inhibitors have succeeded in the clinical trials to date. Exploring fine mechanisms of HSP90 inhibition in cancer cells may shed light on novel therapeutic strategies. Here we found that HSP90 knockdown and continuous inhibition with ganetespib inhibited growth of MCL cells in vitro and in vivo. To our surprise, transient exposure over 12 hours was almost as efficient as continuous exposure, and treatment with ganetespib for 12 hours efficiently inhibited growth and induced G1 cell cycle arrest and apoptosis of MCL cells. Transcriptome analysis complemented by functional studies were performed to define critical MCL signaling pathways that are exceptionally sensitive to HSP90 inhibition and vital to cell fate. Six genes (CDC6, CDC45, MCM4, MCM7, RMI2, and PRIM1) involved in DNA replication and repair were identified as consistently downregulated in three MCL cell lines after transient ganetespib treatment. E2F1, an important transcription factor essential for cell cycle progression, was identified as a ganetespib target mediating transcriptional downregulation of these 6 genes, and its stability was also demonstrated to be maintained by HSP90. This study identifies E2F1 as a novel client protein of HSP90 that is very sensitive and worthy of targeting, and also finds that HSP90 inhibitors may be useful in combination therapies for MCL.
... The pathognomic feature of MCL is the chromosomal translocation t(11;14) (q13;q32) (IGH/CCND1), which is observed in >95% of cases, resulting in the constitutive overexpression of G1-phase cell cycle protein cyclin D1 (CCND1). Additional mutations also work in concert with CCND1 overexpression to exacerbate lymphomagenesis through cell cycle deregulation, potentially leading to more aggressive blastoid or pleomorphic MCL [3]. Although MCL is typically associated with the rapid evolution and aggressive behavior that is resistant to therapy, there exists a subset of MCL cases that follow an indolent and stable clinical course. ...
Article
Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma (NHL) with a dismal prognosis. The pathogenesis of MCL is complex and involves molecular alterations in various genes and pathways including the regulatory elements of the cell cycle machinery and senescence, DNA damage response pathways, and cell survival signals. Currently, Mantle Cell Lymphoma International Prognostic Index (MIPI) score and proliferative gene markers. TP53 and CDKN2A alterations are being used for the prognosis of MCL patients. The molecular profiling performed with various expression studies has paved the way for the identification of novel molecular targets and novel biomarkers not only aid in the diagnosis and prognosis of MCL but also predict the clinical outcome and prognosis. Our patient is a 74-year-old male who came for urinary complaints and routine blood work and revealed leukocytosis and lymphocytosis with abdominal and pelvic lymphadenopathies. Further work-up confirmed the diagnosis of MCL involving peripheral blood, bone marrow, and colon. In our patient, due to aggressive presentation, next generation sequencing was performed to understand the genetic aberrations relevant for MCL. In addition to known markers, we identified genetic mutations in FAT1, IKZF3, and TRAF2. which have never been reported in MCL and could be pathogenic for the aggressive presentation of our patient and thus could be further investigated with in vitro and animal models.
... Mantle cell lymphoma (MCL) primarily occurs among elderly patients with a median age greater than 60 years. 1 Half of these patients are not eligible for standard therapy that includes autologous blood stem cell transplantation due to the presence of comorbidities and to the general performance status. ...
Article
Full-text available
We discuss the case of a 74-year old male patient with mantle cell lymphoma, who faced severe CMV infection after the fifth cycle of first-line chemo-immunotherapy with a dose-reduced bendamustine and rituximab regimen.
... According to the stage of disease MCL cells invade non mantle zone regions within the lymph node and change from a mantle zone to nodular or diffuse growth pattern ending up to effacement of the organ's structure (Jares and Campo, 2008). ...
Thesis
Mantle cell lymphoma (MCL) is an aggressive lymphoid cancer characterised by iterative clinical relapses and short survival. MCL displays complex genetics and hallmarks of misregulated expression of lineage specific genes. We have hypothesized that the latter might result from corruption of H3 lysine 9 trimethylation signaling. By screening for H3K9me3 levels across a cohort of 120 MCL cases, we found global reductions in H3K9me3 in 1/3 of cases. H3K9me3 depletion was linked to underexpression / attenuated activity of SUV39H1 and SETDB1 histone methylases, respectively, and to differential expression of key cancer signatures relating to embryonic/hematopoietic stem cell function, B cell differentiation, and DNA damage response. Targeted deep sequencing did not reveal association to mutations in known epigenetic modifiers, indicating a new, previously-unsuspected role for H3K9me3 in MCL pathogenesis. In keeping with this, knockdown of SUV39H1 increased tumour growth in MCL xenografts while SETDB1 depletion induced G1/S arrest coincident to reprogramming to a pre-B cell phenotype. Taken together this identifies convergence of H3K9me3 signaling pathways to essential targets for MCL disease pathogenesis. These are currently under investigation by H3K9me3 ChIP-seq. Survival analyses in the setting of a prospective clinical trial will establish the prognostic impact of H3K9me3 in MCL.
... Mantle cell lymphoma (MCL) is a highly lethal and aggressive B cell malignancy in the world (Jares and Campo, 2008;Sharma et al., 2010;Pérez-Galán et al., 2011;Jain and Wang, 2019;Yoon et al., 2020). Owing to the lack of effective therapeutic strategies, the median survival time of MCL is only about 4 years after initial diagnosis (Cheah et al., 2016). ...
Article
Full-text available
Mantle cell lymphoma (MCL) is a highly aggressive and heterogeneous B-cell lymphoma. Though Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has shown great efficacy as a single agent for MCL treatment, the real-world use of ibrutinib is still subject to limitations. Our previous study has shown the treatment with HSP90 inhibitor ganetespib can attack major targets of MCL, luckily complementary to ibrutinib’s targets. In this study, transient ganetespib treatment sensitizes MCL cells to ibrutinib as manifested by the significant decrease of IC50 values, percentages of EdU (5-Ethynyl-2′-deoxyuridine) positive cells, and levels of p-AKT and NF-κB after combinational treatment. Additionally, pretreatment with ganetespib enhanced cell cycle arrest induced by ibrutinib at G0/G1 phase and significantly decreased levels of cell cycle promoting proteins CDK2, 4, and 6. Pretreatment with ganetespib also enhanced cell apoptosis induced by ibrutinib through the upregulation of cleaved-caspase 9 and downregulation of BCL-2 in MCL cells at the molecular level. The sequential administration of ganetespib and ibrutinib had similar effects on increasing DNA damage as the transient treatment with ganetespib as demonstrated by the improved percentage of γH2AX and 53BP1 foci. Furthermore, ganetespib significantly increased inhibition of tumor growth mediated by ibrutinib in vivo, confirmed by the changes of the expression levels of Ki-67 and BCL-2 through immunohistochemistry assays. This study indicates that HSP90 inhibitor ganetespib maybe ideal for the combinational use with BTK inhibitor ibrutinib to target major pathogenesis-associated signaling pathways for MCL treatment which may help identify new possibilities for clinical trials.
... It is also possible to simulate alternative rearrangements to better understand the effect of breakpoint variation between patients. Up to 50% of t(11;14) MCL breakpoints are within the so-called 'major translocation cluster' about 120 kbp upstream of CCND1 (Jares and Campo 2008), with the rest scattered throughout a broader 380-kbp region around this. Supplemental Figure S7 shows simulated 4C from two different examples where the Chromosome 14 breakpoint is kept the same but we move the breakpoint on Chromosome 11 to different positions between 11 and 100 kbp upstream of CCND1. We found that, in general, interactions between the gene and the Eµ enhancer are weaker if their genomic separation is larger. ...
Article
Genomic rearrangements are known to result in proto-oncogene deregulation in many cancers, but the link to 3D genome structure remains poorly understood. Here, we used the highly predictive heteromorphic polymer (HiP-HoP) model to predict chromatin conformations at the proto-oncogene CCND1 in healthy and malignant B cells. After confirming that the model gives good predictions of Hi-C data for the nonmalignant human B cell–derived cell line GM12878, we generated predictions for two cancer cell lines, U266 and Z-138. These possess genome rearrangements involving CCND1 and the immunoglobulin heavy locus ( IGH ), which we mapped using targeted genome sequencing. Our simulations showed that a rearrangement in U266 cells where a single IGH super-enhancer is inserted next to CCND1 leaves the local topologically associated domain (TAD) structure intact. We also observed extensive changes in enhancer-promoter interactions within the TAD, suggesting that it is the downstream chromatin remodeling which gives rise to the oncogene activation, rather than the presence of the inserted super-enhancer DNA sequence per se. Simulations of the IGH - CCND1 reciprocal translocation in Z-138 cells revealed that an oncogenic fusion TAD is created, encompassing CCND1 and the IGH super-enhancers. We predicted how the structure and expression of CCND1 changes in these different cell lines, validating this using qPCR and fluorescence in situ hybridization microscopy. Our work demonstrates the power of polymer simulations to predict differences in chromatin interactions and gene expression for different translocation breakpoints.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
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Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
Hematologic malignancies were the first human cancers to be studied in depth at the molecular level, and recent years have seen important advances in treatment. This comprehensive reference book covers the full range of hematologic malignancies, including all subtypes of leukemias, lymphomas, and plasma cell dyscrasias. Authored by internationally known experts, each chapter emphasizes diagnostic work-up, staging, and therapeutic approaches. Up-to-date hematopathology, treatment, and outcomes data are presented in a way which is directly applicable to patient care. Highly illustrated with color images, graphs, flowcharts and treatment algorithms, the book is perfect for quick clinical reference as well as providing detailed reference lists for further study. With its authoritative and practical focus and visually stimulating presentation, this is a key text for hematology and oncology fellows, physicians, oncology nurses, physician assistants and other healthcare workers in the field of oncology.
Chapter
A Case-Based Approach to PET/CT in Oncology describes the role of PET/CT in the diagnosis, staging and monitoring of treatment response in today's practice of oncology. It provides a detailed analysis of over 100 cases occurring in daily clinical practice, emphasizing the central role that PET imaging plays in the care of cancer patients. The text is organized into two sections; Part I guides the reader through general introductory concepts, including basic science, while Part II covers in-depth oncologic applications. Each case is illustrated throughout with full color images and explains the key management issues and the advantages and limitations of the modality. Written by a team of renowned international experts, A Case-Based Approach to PET/CT in Oncology is an invaluable resource for all imaging practitioners, oncologists and nuclear medicine specialists.
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The D‐type cyclins, involved in the regulation of G1 progression of the cell cycle, are expressed in a lineage‐specific manner. Normal hematopoietic cells express cyclin D2 and/or D3. In order to determine whether their expression pattern changes in lymphoid tumors, we examined cyclin D2 and D3 expression in non‐neoplastic and neoplastic lymphoid lesions, using a sensitive immunohistochemical amplification method. Centroblasts in lymphoid follicles of reactive lymph nodes expressed exclusively cyclin D3 and no D2. Interfollicular areas contained scattered cyclin D3 and D2 positive cells. By double staining, cyclin D3 was detected in CD79a positive B cells, CD3 positive T cells and CD68 positive macrophages. Cyclin D2 was present only in CD3 positive T cells. Neoplastic lymphoid lesions included 33 B cell lymphomas, 9 T cell lymphomas and 12 Hodgkin's lymphomas. The B cell lymphomas comprised 9 follicular lymphomas (FL), 1 Burkitt lymphoma (BL), 22 diffuse large cell lymphomas (DL) and 1 chronic lymphocytic leukemia (CLL). All 9 FLs and the single BL expressed exclusively cyclin D3, similarly to germinal center B cells, that represent their cells of origin. Six DLs expressed both cyclin D2 and D3, while 6 expressed only D3. Among the 9 pleomorphic T cell lymphomas, medium and large cell type, 5 expressed cyclin D2. Cyclin D3 was also detected in scattered cells in 4 of 9 cases and was highly expressed in 2 of 9 T cell lymphomas. The majority of Hodgkin's lymphomas expressed both cyclin D2 and D3 in Hodgkin/Reed‐Sternberg (HRS) cells. The high frequency of positive cells indicates that both cyclins were expressed in the same cells. Int. J. Cancer 81:543–550, 1999. © 1999 Wiley‐Liss, Inc.
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The product of the retinoblastoma tumor-suppressor gene (pRB), a nuclear phosphoprotein that regulates transcription factors such as E2F, is involved in cell cycle control and differentiation. Its activity is regulated by phosphorylation; the underphosphorylated form inhibits transcription whereas the highly phosphorylated form is inactive. Cyclin D1 and its associated kinase (CDK 4/6) phosphorylate pRB in vitro, and therefore are thought to contribute to the regulation of pRB function. To examine the effect of cyclin D1 overexpression on pRB in primary tumor tissue, we studied pRB expression in low-grade B- cell neoplasms, with particular regard to mantle cell lymphoma, which is characterized by cyclin D1 (bcl-1) overexpression. pRB expression was studied by immunostaining with a well-characterized anti-pRB antibody; the phosphorylation status of pRB was examined by immunoblots; and the functional binding capacity of pRB was examined by in vitro binding to adenovirus E1A protein. We studied 3 reactive lymph nodes, 28 low grade B-cell lymphomas, 4 cases of hairy cell leukemia (HCL) and 3 plasmacytomas. Reactive lymph nodes showed intense pRB staining of germinal centers, with strongest (2+) staining in the large cells (centroblasts) of the proliferating (dark) zone and weak or no staining of small lymphocytes, including those of the mantle zone. In B- chronic lymphocytic leukemia (B-CLL) (4 cases), follicular lymphoma (3 cases) and mucosa-associated (MALT) lymphoma (3 cases) strong (2+) pRB staining was limited to centroblasts in reactive and neoplastic follicles and occasional proliferation centers, with only faint staining of small lymphoid cells. In contrast, 15 of 16 cases of mantle cell lymphoma showed strong (1–2+) staining of most cells; one blastoid mantle cell lymphoma showed only faint pRB staining. All cases of (HCL) and plasmacytoma showed strong pRB staining. Although most lymphomas with strong pRB expression were cyclin D1(+), three cyclin D1(+) cases showed only weak pRB expression (1 B-CLL, 1 blastoid mantle cell, 1 unclassifiable low grade B-cell lymphoma). Conversely, of the 4 pRB(+) HCLs and 3 pRB(+) plasmacytomas, only 1 of each was cyclin D1(+). pRB appeared to exist primarily in the underphosphorylated (fastest migrating) form on Western blot, despite the fact that cyclin D1 was complexed to CDK4, a form in which it normally phosphorylates pRB. In addition, pRB appeared to be unmutated, because it bound normally to the adenovirus E1A protein and showed nuclear localization by immunostaining. We conclude that most cases of mantle cell lymphoma, HCL, and plasmacytoma show high levels of pRB in contrast to follicle center lymphoma and small lymphocytic lymphoma; however, pRB expression does not appear to be consistently related to cyclin D1 overexpression. The pRB appears to be unmutated and underphosphorylated, and therefore should be in its active form. Our data from primary lymphoma tissue suggests that overexpression of cyclin D1, whereas tumorigenic, does not lead to pRB loss or hyperphosporylation. Thus, the mechanism by which cyclin D1 contributes to tumorigenesis and the significance of the restricted expression of pRB in low-grade lymphoid neoplasms remain to be determined.
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CHK1 gene encodes for a serine/threonine kinase involved in the regulation of cell cycle progression and DNA damage checkpoints. To determine the role of CHK1 in the pathogenesis of lymphoid neoplasms and its relationship to other DNA damage response genes, we have analyzed the gene status, protein, and mRNA expression in a series of tumors and nonneoplastic lymphoid tissues. CHK1 protein and mRNA expression levels were very low in both reactive tissues and resting lymphoid cells, whereas tumor samples showed a variable pattern of expression related to their proliferative activity. However, seven aggressive tumors showed a dissociate pattern of extremely low or negative protein expression in spite of a high proliferative activity. Four of these tumors were diffuse large B-cell lymphomas (DLCLs) with concordant reduced levels of mRNA, whereas one blastoid mantle cell lymphoma (B-MCL) and two DLCLs had relatively normal levels of mRNA. No gene mutations, deletions, or hypermethylation of the promoter region were detected in any of these cases. In all these tumors ATM, CHK2, and p53 genes were wild type. These findings suggest that CHK1 inactivation in NHLs occurs by loss of protein expression in a subset of aggressive variants alternatively to ATM, CHK2, and p53 alterations.Keywords: CHK1, CHK2, p53, checkpoint, lymphoma
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The goal of this study was to analyze the presenting features, natural history, and prognostic factors in 59 patients with well characterized mantle cell lymphoma (MCL). Cases were classified as nodular or diffuse and as typical or blastic variants. Age, performance status (PS), histologic variants, mitotic index (MI), hematologic parameters, tumor extension data, and International Prognostic Index (IPI) were recorded and evaluated for prognosis. The median age of the patients was 63 years (range, 39-83 years), and the male to female ratio was 3:1. Fifty-three patients had typical histology (3 nodular and 50 diffuse), and 6 had the blastic variant. Approximately 95% of patients presented with advanced stage disease (Ann Arbor Stage III-IV). Leukemic expression was observed in 58%. Complete and partial response rates were 19% and 46%, respectively. Parameters associated with lower response rate were Stage IV, high/intermediate or high risk IPI, and increased lactate dehydrogenase (LDH) level. In the logistic regression analysis, high LDH level and Stage IV disease were associated independently with lower response rate. Median survival was 49 months. Parameters associated with a short survival were: poor PS, splenomegaly, B-symptoms, MI > 2.5, leukocyte count > 10 × 109/L, high LDH level, blastic variant, and high/intermediate or high risk IPI. In the Cox proportional hazards regression model, only poor PS (relative risk [RR] = 3.3; P = 0.002), splenomegaly (RR = 2.8; P = 0.007), and MI > 2.5 (RR = 2.4; P = 0.012) were associated with short survival. In this series, patients with MCL presented with advanced stage and extranodal involvement. Only a minority of patients achieved a complete response. The median survival was 4 years, with PS, splenomegaly, and MI being the most important factors predicting survival. These results show clearly that more effective therapies for MCL are needed. Cancer 1998;82:567-75.
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Mantle cell lymphoma (MCL) is a clinicopathologic entity that is difficult to diagnose on histopathologic criteria. Approximately 50% to 70% of MCL contain a t(11;14)(q13;q32) translocation involving the cyclin D1 gene. Irrespective of this rearrangement, almost all MCL show overexpression of the cyclin D1 gene at the mRNA level. Other B-cell non-Hodgkin's lymphomas (NHL) do not show this rearrangement or overexpression of cyclin D1. We developed an immunohistochemical assay to detect overexpression of the cyclin D1 protein on conventional formalin-fixed, paraffin-embedded biopsies using the well-defined monoclonal antibody DCS-6. Expression in tumor cells was compared with expression of cyclin D1 in endothelial cells and fibroblasts. An exclusively nuclear staining pattern was observed. Moreover, expression was directly compared with the expression observed by immunoblot analysis with the same antibody, as well as with mRNA expression and with the occurrence of genomic rearrangements within the BCL-1 locus. Of 13 MCL that were analyzed by immunohistochemistry and immunoblot, 12 showed overexpression with both techniques, whereas no overexpression was observed in 39 other NHL. Of 13 additional MCL studied either by immunohistochemistry or immunoblot, 11 also showed overexpression. Two lymphomas morphologically indistinguishable from MCL but with an aberrant immunophenotype (CD5 negative, CD10 positive) both lacked overexpression of cyclin D1. These results underscore the significance of overexpression of the cyclin D1 protein as a specific marker for MCL. Detection of cyclin D1 overexpression on formalin-fixed, paraffin-embedded tissues using the DCS-6 monoclonal antibody can be applied for routine diagnostic purposes.
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The t(11;14)(q13;q32) translocation and its molecular counterpart bcl-1 rearrangement are frequently associated with mantle cell lymphomas (MCLs) and only occasionally with other variants of B-cell lymphoid malignancies. This translocation seems to activate the expression of PRAD-1/cyclin D1 gene located downstream from the major breakpoint cluster region of this rearrangement. However, the possible overexpression of this gene in other lymphoproliferative disorders independently of bcl-1 rearrangement is unknown. We have examined the overexpression of PRAD-1 gene in a large series of 142 lymphoproliferative disorders including 20 MCLs by Northern blot analysis. Cytogenetic and/or bcl-1 rearrangement analysis with 2 probes (MTC, p94PS) were performed in 28 cases. Strong PRAD-1 overexpression was observed in 19 of the 20 MCLs including 3 gastrointestinal forms and 4 blastic variants. t(11;14) and/or bcl-1 rearrangement was detected in 6 of the 12 MCLs examined. No correlation was found between the different levels of mRNA expression and the pathologic characteristics of the lymphoma. Among chronic lymphoproliferative disorders other than MCL, only 1 atypical chronic lymphocytic leukemia (CLL) with a t(11;14) translocation and bcl-1 rearrangement and the 2 hairy cell leukemias (HCLs) analyzed showed upregulation of PRAD-1 gene. The expression in the 2 HCLs was lower than in MCL, and no bcl-1 rearrangement was observed. These findings indicate that PRAD-1 overexpression is a highly sensitive and specific molecular marker of MCL but it may also be upregulated in some B-CLLs and in HCL.
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Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearrangement and cyclin D1/PRAD-1 gene overexpression. Some aggressive variants have been recognized with a blastic or large cell morphology, higher proliferative activity, and shorter survival. p53 gene mutations in lymphoid neoplasms have been detected mainly in high grade lymphomas and have been associated with tumor progression in follicular and small lymphocytic lymphomas. To determine the role of p53 alterations in MCL, we examined 35 typical and 8 aggressive variants (5 blastic and 3 large cell) of MCLs by a combination of immunohistochemistry, single-strand conformational polymorphism analysis of genomic DNA and/or cDNA obtained by reverse transcriptase-polymerase chain reaction, denaturing gradient gel electrophoresis, and sequencing. Of the 8 aggressive MCLs, 3 (38%) contained missense point mutations in axon 8 codon 278 (Pro --> Leu), exon 8 codon 273 Arg --> His), and exon 5 codon 151 (Pro --> Ser), respectively. A diffuse p53 protein overexpression was observed in more than 50% of the tumor cells in these 3 cases. A fourth blastic MCL also showed strong p53 immunoreactivity. However, no mutations were detected in exons 5-9 in this case. p53 expression was also detected in 10% of the cells in an additional large cell type of MCL and in less than 1% of the cells in 6 typical cases. No mutations were detected in any of these cases or in the remaining cases with no expression of the protein. Four nucleotide changes were observed by single-strand conformational polymorphism analysis in 4 typical MCLs with no overexpression of the protein. Direct sequencing showed that these nucleotide changes were located at exon 6 (1 case), intron 7 (2 cases), and intron 8 (1 case). The changes in exon 6 and intron 7 were known polymorphisms. The nucleotide change in intron 8 was outside splicing sites of the neighboring exons. The overall survival of the 3 patients with p53 mutations (median, 18.3 months) was significantly shorter than that of patients with the nonmutated MCLs (median, 49 months; P < .01). These findings indicate that p53 gene mutations are an infrequent phenomenon in MCLs and are associated with a subset of aggressive variants.
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Mantle cell lymphomas (MCLs) are molecularly characterized by bcl-1 rearrangement and constant cyclin D1 (PRAD-1/CCND1) gene overexpression. Cyclin D1 is a G1 cyclin that participates in the control of the cell cycle progression by interacting with the retinoblastoma gene product (pRb). Inactivation of the Rb tumor suppressor gene has been implicated in the development of different types of human tumors including some high grade non-Hodgkin's lymphomas. To determine the role of the retinoblastoma gene in the pathogenesis of MCLs and its possible interaction with cyclin D1, pRb expression was examined in 23 MCLs including 17 typical and 6 blastic variants by immunohistochemistry and Western blot. Rb gene structure was studied in 13 cases by Southern blot. Cytogenetic analysis was performed in 5 cases. The results were compared with the cyclin D1 mRNA levels examined by Northern analysis, and the proliferative activity of the tumors was measured by Ki-67 growth fraction and flow cytometry. pRb was expressed in all MCLs. The expression varied from case to case (mean, 14.1% of positive cells; range, 1.3 to 42%) with a significant correlation with the proliferative activity of the tumors (mitotic index r = 0.85; Ki-67 r = 0.7; S phase = 0.73). Blastic variants showed higher numbers of pRb-positive cells (mean, 29%) than the typical cases (10%; P < 0.005) by immunohistochemistry and, concordantly, higher levels of expression by Western blot. In addition, the blastic cases also had an increased expression of the phosphorylated protein. No alterations in Rb gene structure were observed by Southern blot analysis. Cyclin D1 mRNA levels were independent of pRb expression and the proliferative activity of the tumors. These findings suggest that pRb in MCLs is normally regulated in relation to the proliferative activity of the tumors. Cyclin D1 overexpression may play a role in the maintenance of cell proliferation by overcoming the suppressive growth control of pRb.
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Mutations of the p53 tumor suppressor gene have been described in several subtypes of non-Hodgkin's lymphoma, but the incidence of p53 mutations in mantle cell lymphoma (MCL) is unknown. We hypothesized that cases of MCL with a variant or high-grade cytology would have a higher likelihood of p53 mutations than typical MCL. We were also interested in the prognostic significance of p53 mutations in MCL. Therefore, a series of 53 well-characterized cases of MCL with DNA from 62 tissue samples were analyzed by the polymerase chain reaction with denaturing gradient gel electrophoresis for exons 5-8 of p53. Immunoperoxidase studies with the antibody DO-7 to p53 protein were also performed on frozen sections. We found mutations of the p53 gene in 8 of the 53 cases (15%) of MCL. Missense mutations predominated, and 50% of the mutations occurred at known p53 hotspot codons. Of 21 cases with variant cytology (ie, anaplastic or blastic), 6 (28.6%) had p53 mutations as compared with only 2 of 32 cases (6.3%) with typical MCL cytology (P = .05), and p53 mutations preceded the development of variant cytology in 2 patients. Overexpression of p53 protein was observed in 6 of the 8 cases (75%) with p53 mutations and in none of the 45 wild-type cases. The median survival of the cases with mutant p53 was only 1.3 years (all died), whereas the median survival of cases with germline p53 was 5.1 years (P = .023). These results suggest that mutations of p53 may be one mechanism involved in the development of variant forms of MCL and indicate that p53 mutations in MCL predict a poor prognosis.
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Several hematologic malignancies are associated with specific chromosomal translocations. Because of the dispersed distribution, chromosomal breakpoints may be difficult to detect using molecular techniques. We present a new application of a recently developed method, DNA fiber fluorescence in situ hybridization (fiber FISH), which allows direct visualization and mapping of chromosomal breakpoints. We tested this method for detection of the t(11;14)(q13;q32) translocation in mantle cell lymphoma. In DNA fiber FISH, a series of fluorochrome-labeled DNA probes covering several hundreds of kilobasepairs is hybridized to linear DNA molecules (or fibers) prepared from frozen tissue or intact cells. By using alternate fluorescent colors, a potential breakpoint region is stained in a color barcode pattern. Breaks in this region will split the barcode in two complementary parts, from which the breakpoint position can be derived. We used a 250-kb barcode covering the BCL-1 locus to detect 11q13 breakpoints in 20 well-characterized mantle cell lymphomas. A t(11;14) was shown by cohybridization of these probes with probes for the Ig heavy chain locus at 14q32. In 18 of 20 mantle cell lymphomas, a breakpoint within the 11q13/BCL-1 barcode was shown by the presence of multiple, complementary translocation products. Fusion of 11q13 and 14q32 sequences on single fibers indicating t(11;14)(q13;q32) was found in all 18 breakpoint-positive mantle cell lymphomas. In one additional case, fusion of an intact 11q13 barcode with 14q32 sequences indicated a breakpoint 100 kb centromeric of the major translocation cluster of BCL-1. Within the 120-kb region of BCL-1, breakpoints were widely scattered. This explains why, so far, a BCL-1 breakpoint had been detected by Southern blot analysis in only 10 of 19 cases. DNA fiber FISH analysis showed a t(11;14) in 95% of mantle cell lymphoma. The results indicate that DNA fiber FISH is a rapid, simple, and equally powerful method for detection of clustered and dispersed translocation breakpoints.
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The association of cdk4 with D-type cyclins to form functional kinase complexes is comparatively inefficient. This has led to the suggestion that assembly might be a regulated step. In this report we demonstrate that the CDK inhibitors p21(CIP), p27(KIP), and p57(KIP2) all promote the association of cdk4 with the D-type cyclins. This effect is specific and does not occur with other cdk inhibitors or cdk-binding proteins. Both in vivo and in vitro, the abundance of assembled cdk4/cyclin D complex increases directly with increasing inhibitor levels. The promotion of assembly is not attributable to a simple cell cycle block and requires the function of both the cdk and cyclin-binding domains. Kinetic studies demonstrate that p21 and p27 lead to a 35- and 80-fold increase in K(a), respectively, mostly because of a decrease in K(off). At low concentrations, p21 promotes the assembly of active kinase complexes, whereas at higher concentrations, it inhibits activity. Moreover, immunodepletion experiments demonstrate that most of the active cdk4-associated kinase activity also associates with p21. To confirm these results in a natural setting, we examine the assembly of endogenous complexes in mammary epithelial cells after release from a G(0) arrest. In agreement with our other data, cyclin D1 and p21 bind concomitantly to cdk4 during the in vivo assembly of cdk4/cyclin D1 complexes. This complex assembly occurs in parallel to an increase in cyclin D1-associated kinase activity. Immunodepletion experiments demonstrate that most of the cellular cyclin D1-associated kinase activity is also p21 associated. Finally, we find that all three CIP/KIP inhibitors target cdk4 and cyclin D1 to the nucleus. We suggest that in addition to their roles as inhibitors, the p21 family of proteins, originally identified as inhibitors, may also have roles as adaptor proteins that assemble and program kinase complexes for specific functions.
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In mantle cell lymphoma (MCL), in addition to the characteristic t(11;14)(q13;q32), rearrangements on the 3' side of the cyclin D1 gene have been described. In a series of 32 MCL we found three cases with 3'-rearrangements by Southern blot analysis with a probe representing the 3' untranslated region of the cyclin D1 gene. All three were characterized by the absence of the 4.5 kb transcript, and instead, two cases showed overexpression of the 1.7 kb and a third case (MCLp14) an aberrant 2.5 kb transcript. At the genomic level, fine mapping experiments showed in the 3' untranslated region a 2 kb deletion in MCLp14 and a breakpoint in the other two cases. Fiber FISH analysis showed that in all three cases the 3' aberration co-exists with a regular t(11;14) breakpoint 5' of cyclin D1 on a single allele. Fiber FISH analysis of 16 additional MCL revealed two other such cases with breakpoints 5' and 3' of cyclin D1. These mono-allelic aberrations affecting the cyclin D1 gene suggest that the t(11;14) as a first step switches on transcription, and then sequences in the untranslated region of cyclin D1 are affected to stabilize the message.
Article
Although mantle cell lymphoma (MCL) is considered a distinctive disease entity within non‐Hodgkin's lymphoma (NHL), the cytology and growth pattern of MCL can be quite variable and the clinical significance of these features is unclear. Also, the role of anthracyclines in the management of MCL is unclear. Therefore, we examined our experience with MCL in an effort to clarify these important issues. We identified 68 patients with MCL who were evaluated clinically and treated by the Nebraska Lymphoma Study Group. Treatment consisted of combination chemotherapy containing an anthracycline in 76% of the patients. The cases were grouped by blastic or lymphocytic cytology, and the latter were divided by growth pattern into nodular (or mantle‐zone) and diffuse types. The clinical and pathological variables were then evaluated for their prognostic value. The median overall survival (OS) and failure‐free survival (FFS) for the entire group were 38 months and 12 months, respectively, and there was no survival advantage for those who received an anthracycline. The cases were grouped as follows: blastic type, 26%; nodular lymphocytic type, 44%; and diffuse lymphocytic type, 30%. Both the cytology and pattern of growth were predictive of OS and FFS. The median OS was as follows: blastic type, 55 months; nodular lymphocytic type, 50 months; and diffuse lymphocytic type, 16 months (P = 0.0038). The clinical features that predicted for a shorter survival included bone marrow involvement, advanced stage disease, B symptoms, a poor performance score, and the International Prognostic Index. We conclude that new therapeutic approaches, with the patients stratified by histologic type and clinical prognostic factors, are clearly needed for MCL. Am. J. Hematol. 64:190–196, 2000. © 2000 Wiley‐Liss, Inc.
Article
Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.
Article
Deletions involving the long arm of chromosome 11 (11q) have been recently found as recurrent chromosome aberrations in mantle cell lymphoma (MCL). In the current study, the incidence and molecular extent of 11q deletions were analyzed in a series of 81 MCL by fluorescence in situ hybridization with probes from a contiguous set of yeast artificial chromosomes (YACs). Loss of chromosome 11 material was observed in 37 of 81 cases (46%). The minimally deleted segment comprised YAC 801e11 containing the ATM gene. To further narrow the minimal region of loss, P1-derived artificial chromosomes mapping to the critical region were isolated and used as probes in cases without aberrations detectable with YACs. This allowed the identification of an ATM deletion that was beyond the resolution of YAC probes. The identification of a minimally deleted segment affecting ATM suggests a pathogenic role of ATMas a tumor suppressor gene in MCL.
Article
Mantle cell lymphoma (MCL) is a clinicopathologic entity that is difficult to diagnose on histopathologic criteria. Approximately 50% to 70% of MCL contain a t(11;14)(q13;q32) translocation involving the cyclin D1 gene. Irrespective of this rearrangement, almost all MCL show overexpression of the cyclin D1 gene at the mRNA level. Other B-cell non-Hodgkin's lymphomas (NHL) do not show this rearrangement or overexpression of cyclin D1. We developed an immunohistochemical assay to detect overexpression of the cyclin D1 protein on conventional formalin-fixed, paraffin-embedded biopsies using the well-defined monoclonal antibody DCS-6. Expression in tumor cells was compared with expression of cyclin D1 in endothelial cells and fibroblasts. An exclusively nuclear staining pattern was observed. Moreover, expression was directly compared with the expression observed by immunoblot analysis with the same antibody, as well as with mRNA expression and with the occurrence of genomic rearrangements within the BCL-1 locus. Of 13 MCL that were analyzed by immunohistochemistry and immunoblot, 12 showed overexpression with both techniques, whereas no overexpression was observed in 39 other NHL. Of 13 additional MCL studied either by immunohistochemistry or immunoblot, 11 also showed overexpression. Two lymphomas morphologically indistinguishable from MCL but with an aberrant immunophenotype (CD5 negative, CD10 positive) both lacked overexpression of cyclin D1. These results underscore the significance of overexpression of the cyclin D1 protein as a specific marker for MCL. Detection of cyclin D1 overexpression on formalin-fixed, paraffin-embedded tissues using the DCS-6 monoclonal antibody can be applied for routine diagnostic purposes.
Article
Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearrangement and cyclin D1 gene overexpression. Some aggressive variants of MCL have been described with blastic or large cell morphology, higher proliferative activity, and shorter survival. The cyclin-dependent kinase inhibitors (CDKIs) p21Waf1 and p16INK4a have been suggested as candidates for tumor-suppressor genes. To determine the role of p21Waf1 and p16INK4a gene alterations in MCLs, we examined the expression, deletions, and mutations of these genes in a series of 24 MCLs, 18 typical, and 6 aggressive variants. Loss of expression and/or deletions of p21Waf1 and p16INK4a genes were detected in 4 (67%) aggressive MCLs but in none of the typical variants. Two aggressive MCLs showed a loss of p16INK4a expression. These cases showed homozygous deletions of p16INK4a gene by Southern blot analysis. An additional aggressive MCL in which expression could not be examined showed a hemizygous 9p12 deletion. Loss of p21Waf1 expression at both protein and mRNA levels was detected in an additional aggressive MCL. No p21Waf1 gene deletions or mutations were found in this case. The p21Waf1 expression in MCLs was independent of p53 mutations. The two cases with p53 mutations showed p21Waf1 and p16INK4a expression whereas the 4 aggressive MCLs with p16INK4a and p21Waf1 gene alterations had a wild-type p53. p21Waf1 and p16INK4a were expressed at mRNA and protein levels in all typical MCLs examined. No gene deletions or point mutations were found in typical variants. Two typical MCLs showed an anomalous single-stranded conformation polymorphism corresponding to the known polymorphisms at codon 148 of p16INK4a gene and codon 31 of p21Waf1 gene. These findings indicate that p21Waf1 and p16INK4a alterations are rare in typical MCLs but the loss of p21Waf1 and p16INK4a expression, and deletions of p16INK4a gene are associated with aggressive variants of MCLs, and they occur in a subset of tumors with a wild-type p53 gene.
Article
The t(11;14)(q13;q32) translocation and its molecular counterpart bcl-1 rearrangement are frequently associated with mantle cell lymphomas (MCLs) and only occasionally with other variants of B-cell lymphoid malignancies. This translocation seems to activate the expression of PRAD-1/cyclin D1 gene located downstream from the major breakpoint cluster region of this rearrangement. However, the possible overexpression of this gene in other lymphoproliferative disorders independently of bcl-1 rearrangement is unknown. We have examined the overexpression of PRAD-1 gene in a large series of 142 lymphoproliferative disorders including 20 MCLs by Northern blot analysis. Cytogenetic and/or bcl-1 rearrangement analysis with 2 probes (MTC, p94PS) were performed in 28 cases. Strong PRAD-1 overexpression was observed in 19 of the 20 MCLs including 3 gastrointestinal forms and 4 blastic variants. t(11;14) and/or bcl-1 rearrangement was detected in 6 of the 12 MCLs examined. No correlation was found between the different levels of mRNA expression and the pathologic characteristics of the lymphoma. Among chronic lymphoproliferative disorders other than MCL, only 1 atypical chronic lymphocytic leukemia (CLL) with a t(11;14) translocation and bcl-1 rearrangement and the 2 hairy cell leukemias (HCLs) analyzed showed upregulation of PRAD-1 gene. The expression in the 2 HCLs was lower than in MCL, and no bcl-1 rearrangement was observed. These findings indicate that PRAD-1 overexpression is a highly sensitive and specific molecular marker of MCL but it may also be upregulated in some B-CLLs and in HCL.
Article
To clarify whether mantle cell lymphomas (MCLs) are related to naive pre-germinal center B cells (expressing nonmutated rearranged VH genes) or to germinal center-derived memory B cells (expressing mutated rearranged VH genes), clonal IgH gene rearrangements using DNA from six MCLs were polymerase chain reaction (PCR)-amplified and analyzed for the presence of somatic mutations. For comparison, six cases of B- chronic lymphocytic leukemia (B-CLL) known to display nonmutated rearranged VH genes and six cases of follicle center lymphomas (FCLs) known to display mutated rearranged VH genes were included in our study. The VH region sequences of the six MCLs showed, like those of the six B-CLL cases, no or very little somatic mutations, in contrast to the VH sequences of the six FCL cases, all of which were highly mutated. This is indicative of MCL, like B-CLL, being derived from naive pre-germinal center B cells and furthermore underscores the postulated relationship of MCLs with the B cells of the normal follicular mantle zone because it has recently been shown that this mantle zone is solely or at least largely composed of naive (nonmutated) B cells.
Article
Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.
Article
B-lymphocyte stimulator (BLyS), a relatively recently recognized member of the tumor necrosis factor ligand family (TNF), is a potent cell-survival factor expressed in many hematopoietic cells. BLyS binds to 3 TNF-R receptors, TACI, BCMA, BAFF-R, to regulate B-cell survival, differentiation, and proliferation. The mechanisms involved in BLYS gene expression and regulation are still incompletely understood. In this study, we examined BLYS gene expression, function, and regulation in B-cell non-Hodgkin lymphoma (NHL-B) cells. Our studies indicate that BLyS is constitutively expressed in aggressive NHL-B cells, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL), playing an important role in the survival and proliferation of malignant B cells. We found that 2 important transcription factors, NF-kappaB and NFAT, are involved in regulating BLyS expression through at least one NF-kappaB and 2 NFAT binding sites in the BLYS promoter. We also provide evidence suggesting that the constitutive activation of NF-kappaB and BLyS in NHL-B cells forms a positive feedback loop associated with lymphoma cell survival and proliferation. Our findings indicate that constitutive NF-kappaB and NFAT activations are crucial transcriptional regulators of the BLyS survival pathway in malignant B cells that could be therapeutic targets in aggressive NHL-B.
Article
The relative levels of cyclin D1 (CCND1) (a) and (b) transcripts were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and found to vary according to the tissue origin in both control and tumor samples. A fivefold overexpression of both isoforms was observed in 28/38 cases of mantle cell lymphoma (MCL) and of only one isoform in 10/38 MCL. No correlation was observed between expression of cyclin D1 isoforms and CCND1 genotype at position 870.
Article
We used gene expression profiling to establish a molecular diagnosis of mantle cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of survival of these patients. An MCL gene expression signature defined a large subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1 expression. A precise measurement of tumor cell proliferation, provided by the expression of proliferation signature genes, identified patient subsets that differed by more than 5 years in median survival. Differences in cyclin D1 mRNA abundance synergized with INK4a/ARF locus deletions to dictate tumor proliferation rate and survival. We propose a quantitative model of the aberrant cell cycle regulation in MCL that provides a rationale for the design of cell cycle inhibitor therapy in this malignancy.
Article
Chk2 is a novel checkpoint kinase isolated as a human homologue of yeast Cds1/Rad53.[1][1] Recent analyses have revealed that it is among key molecules signaling DNA damage via the ATM protein kinase to p53.[1][1] [2][2] Of great interest is the report that germ line mutations of the Chk2 gene are
Article
Mantle cell lymphoma (MCL) is a low grade B-cell lymphoma; patients with this lymphoma have widespread nodal disease at the time of diagnosis, although local extranodal disease has also been reported in some cases. It is uncertain whether these two disease are identical. To determine the relationship between MCL and extrnodal lymphoma with a morphology similar to that of MCL, we compared clinical and immunohistological findings of 17 patients with MCL to those of 54 patients with other low grade B-cell lymphoma including 15 patients with extranodal lymphoma. The overexpression of PRAD1 gene and the expression of immunoglobulin shared idiotypes were also studied in these lymphomas. The patients with MCL had advanced disease with generalized lymphadenopathy on admission, a CD5+CD10-IgD+ phenotype, and PRAD1 gene overexpression. In contrast, the patients with extranodal lymphoma had localized disease on admission, a CD5-CD10-IgD- phenotype, and lack of PRAD1 expression. The patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) also showed findings indicating a distinctive disease entity. The expression of shared idiotypes, which may be a serologic marker for little or no somatic mutation, were detected in only 4 of 27 FL patients, 10 of 13 MCL, 4 of 6 CLL, and 9 of 14 extranodal lymphomas. These finding suggest that 1) MCL is nodal disease and differs from extranodal lymphoma, 2) there are four distinctive disease entities within low grade B-cell lymphoma: MCL, CLL, FL, and extranodal lymphoma, and 3) MCL, CLL, and extranodal lymphoma are derived from pre-germinal center cell or cell non-entering germinal center, although FL is derived from germinal center cell.
Article
B cells are characterized by the dual expression of CD40 and Fas receptors, which can mediate their survival and death, respectively. The balance between the dynamically opposing functions of these two receptors is important for B-cell selection, maturation and homeostasis. We found that mantle cell lymphoma (MCL) cells had a high level of CD40 and low or absent level of Fas, therefore favouring the CD40 cell survival pathway. Exogenous Fas ligand had no effect on MCL cells, whereas exogenous CD40 ligand enhanced their survival and rescued them from fludarabine-induced apoptosis. Our data raise the possibility that the prolonged survival of MCL cells in vivo may be explained by the unbalanced expression of Fas and CD40.
Article
Until now, few data on additional chromosomal aberrations in t(11;14)-positive mantle cell lymphomas (MCLs) have been published. We analyzed 39 t(11;14)-positive MCLs by either comparative genomic hybridization (CGH; n = 8), fluorescence in situ hybridization (FISH) with a set of DNA probes detecting the most frequent aberrations in B-cell neoplasms (n = 12), or both techniques (n = 19). The t(11;14) was present in all cases. In 37 of 39 cases, chromosomal imbalances were found. In 27 cases, complex karyotypes, i.e., ≥ 3 aberrations, were identified. The most frequent aberrations were losses of 13q14–21 or 13q32–34 (27 cases), 9p21 (16 cases), and 11q22–23 (12 cases) and gains of 3q26–29 (19 cases), 8q22–24 (11 cases), and 18q21–22 (9 cases). In 26% of cases (7 of 27) analyzed by CGH, a total of 10 high-level DNA amplifications were identified. Although in comparison with B-cell chronic lymphopcytic leukemia (B-CLL) MCL is characterized by a much higher complexity of chromosomal aberrations, there are striking similarities: 13q14 deletions were identified in more than 50% of both MCL and B-CLL cases. In contrast, in our CGH database containing 293 B-cell lymphomas, this aberration was found in only 11% of other nodal lymphomas. Even more strikingly, 11q deletions, which are present in 20%–30 % of MCL and B-CLL, were found very rarely in other nodal B-cell lymphomas (CGH: 1 of 208 cases; FISH: 1 of 69 cases). These data show that MCL is characterized by specific secondary aberrations and that there may be similarities in the pathogenesis of MCL and B-CLL. Genes Chromosomes Cancer 27:285–294, 2000. © 2000 Wiley-Liss, Inc.
Article
Mantle cell lymphoma (MCL) is associated with a very unfavourable clinical course. This is particularly true for mantle cell lymphoma of the blastoid subtype (MCL-b). In order to define prognostic factors, we analysed the impact of immunoglobulin heavy chain variable (IgVH) gene somatic hypermutations on clinical outcome in a series of 21 cases of morphologically, phenotypically, and genotypically well-characterized MCL-b. Testing and estimation were performed using log-rank statistics and displayed on Kaplan–Meier graphs. Thirteen of 21 cases of MCL-b revealed a homology rate of ≥99% compared to IgVH germ-line sequences in the databases and were scored as non-mutated. Eight of 21 cases (38%) of MCL-b were mutated. In MCL-b the mutation frequency was usually low and the mutation pattern was only rarely antigen-selected, in contrast to a control group of 11 cases with morphologically almost identical, but phenotypically and genotypically clearly distinguishable, diffuse large B cell lymphoma, derived, most likely, from germinal centre B cells. In our series of 21 MCL-b, positive IgVH mutational status, irrespective of varying homology thresholds, had no statistically significant prognostic impact on event-free or overall survival. However, mutated MCL-b tended to present more frequently at an earlier stage and without bone marrow involvement and to show lower rates of relapse and death, resulting in a more favourable clinical outcome. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Article
The D-type cyclins, involved in the regulation of G1 progression of the cell cycle, are expressed in a lineage-specific manner. Normal hematopoietic cells express cyclin D2 and/or D3. In order to determine whether their expression pattern changes in lymphoid tumors, we examined cyclin D2 and D3 expression in non-neoplastic and neoplastic lymphoid lesions, using a sensitive immunohistochemical amplification method. Centroblasts in lymphoid follicles of reactive lymph nodes expressed exclusively cyclin D3 and no D2. Interfollicular areas contained scattered cyclin D3 and D2 positive cells. By double staining, cyclin D3 was detected in CD79a positive B cells, CD3 positive T cells and CD68 positive macrophages. Cyclin D2 was present only in CD3 positive T cells. Neoplastic lymphoid lesions included 33 B cell lymphomas, 9 T cell lymphomas and 12 Hodgkin's lymphomas. The B cell lymphomas comprised 9 follicular lymphomas (FL), 1 Burkitt lymphoma (BL), 22 diffuse large cell lymphomas (DL) and 1 chronic lymphocytic leukemia (CLL). All 9 FLs and the single BL expressed exclusively cyclin D3, similarly to germinal center B cells, that represent their cells of origin. Six DLs expressed both cyclin D2 and D3, while 6 expressed only D3. Among the 9 pleomorphic T cell lymphomas, medium and large cell type, 5 expressed cyclin D2. Cyclin D3 was also detected in scattered cells in 4 of 9 cases and was highly expressed in 2 of 9 T cell lymphomas. The majority of Hodgkin's lymphomas expressed both cyclin D2 and D3 in Hodgkin/Reed-Sternberg (HRS) cells. The high frequency of positive cells indicates that both cyclins were expressed in the same cells. Int. J. Cancer 81:543–550, 1999. © 1999 Wiley-Liss, Inc.
Article
The proto-oncogene PRAD1 (parathyroid adenoma 1) on chromosome 11q13 was found to be overexpressed in all five B-cell lines with t(11;14)(q13;q32) translocation tested. One B-cell lymphoma and four myeloma cell lines with this translocation demonstrated more than 10-fold overexpression as determined by Northern blot analysis, when compared with normal lymphoid tissues such as thymus, spleen and lymph node. Hematopoietic cell lines without the translocation were also examined, but none of these demonstrated the overexpression, confirming that overexpression of the PRAD1 gene is associated with t(11;14) translocation. A truncated form of mRNA was seen in one of five cell lines with the translocation, SP-49. Hybridization with different regions of the PRAD1 cDNA revealed that the truncated form of mRNA retained the coding region but had lost the 3' untranslated region. Southern blot analysis demonstrated a gene rearrangement in this SP-49 cell line. To study the genetic alteration responsible for the truncated form of mRNA in this cell line, the rearranged allele as well as the germline allele were cloned. The restriction map revealed that the rearranged portion was at the 3' end of the PRAD1 gene, eliminating the mRNA-destabilizing signal AUUUA. Human-rodent hybrid cell analysis demonstrated that the region introduced 3' of PRAD1 was derived from chromosome 11, suggesting that the PRAD1 gene region is deleted at the 3' end. Over-expression of the PRAD1 gene in association with t(11;14)(q13;q32) translocation suggested that in these cases the regulation of PRAD1 was altered by the juxtaposed gene, most likely the immunoglobulin heavy-chain gene from chromosome 14.
Article
A cDNA library prepared from a human glioblastoma cell line has been introduced into a budding yeast strain that lacks CLN1 and CLN2 and is conditionally deficient for CLN3 function. We rescued a gene that we call cyclin D1. It is related to A-, B-, and CLN-type cyclins, but appears to define a new subclass within the cyclin gene family. Transcription of the cyclin D1 gene gives rise to two major transcripts through alternative polyadenylation. The cyclin D1 gene transcript and its 34 kd product are both abundant in the glioblastoma cell line of origin.
Article
The histological, immunological and molecular characteristics of mantle cell lymphoma have only recently been delineated. Amongst these characteristics possible factors of prognostic significance include histological growth pattern and blastoid change. 66 previously untreated cases of mantle cell lymphoma were identified in a retrospective analysis. In 50 cases serial biopsies had been taken during the disease and in 20 cases autopsies had been performed. Besides established factors of prognostic significance, histological growth pattern and blastoid change were examined. 32 patients achieved an initial complete remission or good partial remission with most cases relapsing or progressing within 2 years. The median survival was 36 months. Factors predicting a poor outcome were high presenting stage, age > 70, low sodium, low albumin and splenomegaly. Blastoid transformation was also a poor prognostic feature, occurring in 32% of cases during life and in 70% of autopsies. Histological growth pattern had no influence on outcome. This study emphasises the difficulties in treating mantle cell lymphoma and the high frequency and prognostic importance of histological transformation.
Article
Using Northern blotting and PCR analysis of cDNA derived from a range of cell lines and tissues, alternate splicing of the cyclin D1 gene (CCND1) mRNA has been demonstrated. The variant transcript shows no splicing at the downstream exon 4 boundary, encoding a protein with an altered carboxy-terminal domain. Investigation of mRNA extracted from mononuclear cells, lung tumour and normal tissue suggests that both transcripts are invariably expressed. However, splicing to produce the two forms of mRNA is modulated, in the heterozygote, by a frequent A/G polymorphism located within the splice donor region of exon 4. Preliminary analysis of patients with resectable non-small cell lung cancer suggests that genotype is associated with shortened event free survival and greater risk of local relapse.
Article
To clarify whether mantle cell lymphomas (MCLs) are related to naive pre-germinal center B cells (expressing nonmutated rearranged VH genes) or to germinal center-derived memory B cells (expressing mutated rearranged VH genes), clonal IgH gene rearrangements using DNA from six MCLs were polymerase chain reaction (PCR)-amplified and analyzed for the presence of somatic mutations. For comparison, six cases of B-chronic lymphocytic leukemia (B-CLL) known to display nonmutated rearranged VH genes and six cases of follicle center lymphomas (FCLs) known to display mutated rearranged VH genes were included in our study. The VH region sequences of the six MCLs showed, like those of the six B-CLL cases, no or very little somatic mutations, in contrast to the VH sequences of the six FCL cases, all of which were highly mutated. This is indicative of MCL, like B-CLL, being derived from naive pre-germinal center B cells and furthermore underscores the postulated relationship of MCLs with the B cells of the normal follicular mantle zone because it has recently been shown that this mantle zone is solely or at least largely composed of naive (nonmutated) B cells.
Article
The chromosomal translocation t(11:14) is associated with human lymphoid neoplasia affecting centrocytic B-cells of intermediate differentiation. As a consequence the cyclin D1 (bcl-1) gene is juxtaposed to the immunoglobulin heavy chain enhancer E mu. To show that transcriptional activation of cyclin D1 is causally involved in the generation of B-cell neoplasia we have generated transgenic mice that carry a cyclin D1 gene under the transcriptional control of the E mu element. E mu cyclin D1 transgenic mice show only very subtle alterations in the cycling behaviour of B-cell populations in the bone marrow compared with normal mice and do not develop lymphoid tumours. However, E mu-directed coexpression of cyclin D1 and N-MYC or L-MYC in double transgenic mice reveals a strong cooperative effect between MYC and cyclin D1 provoking the rapid development of clonal pre-B and B-cell lymphomas. Interestingly, crossing of cyclin D1 transgenic mice with E mu L-myc transgenics that express their transgene in both B- and T-cells but predominantly develop T-cell tumours leads in double transgenics exclusively to B-cell neoplasia. The data presented here demonstrate that transcriptional activation of cyclin D1 can oncogenically transform B-cells in concert with a myc gene. They establish cyclin D1 as a proto-oncogene whose activity appears to depend on a specific cell type as well as on a specific cooperating partner and link disturbances in the regulation of cell cycle progression to the development of human malignancies.
Article
In non-Hodgkin's lymphomas, CNS involvement is highly dependent on the histology of the lymphoma. Mantle-cell lymphoma (MCL) is a lymphoma type with distinctive histologic, biologic, and clinical features in which CNS involvement has only been rarely described. The purpose of this report is to describe the incidence, clinical characteristics, and outcome of CNS infiltration in patients with MCL seen at a single institution. Twenty-two patients with MCL, who account for 6% of all patients with nodal lymphomas diagnosed and monitored at a university hospital from 1987 to 1994, were studied. Analysis of the incidence of CNS involvement by the disease was performed. Five of 22 patients (22%; exact 95% confidence interval [CI], 7.8% to 45.4%) with MCL developed CNS involvement at a median of 18 months (range, 6 to 59) from diagnosis. All of these patients presented with poor MCL histologic subtypes and advanced disease. When the CNS infiltration became apparent, all of the patients displayed neurologic signs and had lymphoid cells consistent with the diagnosis of MCL in the CSF. In most of the cases, CNS infiltration was part of resistant disease or generalized relapse and had an ominous significance. The incidence of CNS involvement in MCL might be higher than previously recognized. The frequency of CNS infiltration in MCL deserves to be investigated in other series and, if a high incidence is confirmed, the risk factors, mechanisms, and clinical implications of such a complication should be further studied.
Article
The product of the retinoblastoma tumor-suppressor gene (pRB), a nuclear phosphoprotein that regulates transcription factors such as E2F, is involved in cell cycle control and differentiation. Its activity is regulated by phosphorylation; the underphosphorylated form inhibits transcription whereas the highly phosphorylated form is inactive. Cyclin D1 and its associated kinase (CDK 4/6) phosphorylate pRB in vitro, and therefore are thought to contribute to the regulation of pRB function. To examine the effect of cyclin D1 overexpression on pRB in primary tumor tissue, we studied pRB expression in low-grade B-cell neoplasms, with particular regard to mantle cell lymphoma, which is characterized by cyclin D1 (bcl-1) overexpression. pRB expression was studied by immunostaining with a well-characterized anti-pRB antibody; the phosphorylation status of pRB was examined by immunoblots; and the functional binding capacity of pRB was examined by in vitro binding to adenovirus E1A protein. We studied 3 reactive lymph nodes, 28 low grade B-cell lymphomas, 4 cases of hairy cell leukemia (HCL) and 3 plasmacytomas. Reactive lymph nodes showed intense pRB staining of germinal centers, with strongest (2+) staining in the large cells (centroblasts) of the proliferating (dark) zone and weak or no staining of small lymphocytes, including those of the mantle zone. In B-chronic lymphocytic leukemia (B-CLL) (4 cases), follicular lymphoma (3 cases) and mucosa-associated (MALT) lymphoma (3 cases) strong (2+) pRB staining was limited to centroblasts in reactive and neoplastic follicles and occasional proliferation centers, with only faint staining of small lymphoid cells. In contrast, 15 of 16 cases of mantle cell lymphoma showed strong (1-2+) staining of most cells; one blastoid mantle cell lymphoma showed only faint pRB staining. All cases of (HCL) and plasmacytoma showed strong pRB staining. Although most lymphomas with strong pRB expression were cyclin D1(+), three cyclin D1(+) cases showed only weak pRB expression (1 B-CLL, 1 blastoid mantle cell, 1 unclassifiable low grade B-cell lymphoma). Conversely, of the 4 pRB(+) HCLs and 3 pRB(+) plasmacytomas, only 1 of each was cyclin D1(+). pRB appeared to exist primarily in the underphosphorylated (fastest migrating) form on Western blot, despite the fact that cyclin D1 was complexed to CDK4, a form in which it normally phosphorylates pRB. In addition, pRB appeared to be unmutated, because it bound normally to the adenovirus E1A protein and showed nuclear localization by immunostaining. We conclude that most cases of mantle cell lymphoma, HCL, and plasmacytoma show high levels of pRB in contrast to follicle center lymphoma and small lymphocytic lymphoma; however, pRB expression does not appear to be consistently related to cyclin D1 overexpression. The pRB appears to be unmutated and underphosphorylated, and therefore should be in its active form. Our data from primary lymphoma tissue suggests that overexpression of cyclin D1, whereas tumorigenic, does not lead to pRB loss or hyperphosporylation. Thus, the mechanism by which cyclin D1 contributes to tumorigenesis and the significance of the restricted expression of pRB in low-grade lymphoid neoplasms remain to be determined.
Article
Bone marrow trephine and peripheral blood smears taken at diagnosis of 55 cases of well-documented mantle cell lymphomas were reviewed in order to analyse the leukaemic involvement in this non-Hodgkin's lymphoma: its incidence, morphological characteristics and prognostic significance. A median survival of 36 months was found. The median age was 61 and the male to female ratio was 4:1. Morphologically 7 cases presented with a mantle zone pattern, all the others had a diffuse pattern. Involvement of the bone marrow was found in 58% and a trend for prolonged survival in patients with a negative trephine was seen. An absolute lymphocytosis above 10,000 mu l was found at diagnosis in 5 cases (10%) and had a statistically significant impact on survival. An additional 5 cases developed frank leukaemia during the course of the disease and died within 1 to 6 months of this evolution, suggesting that marked lymphocytosis is more a terminal event associated with an extremely poor prognosis than a presenting symptom. Finally we identified an additional parameter with statistically prognostic significance, namely, the presence of atypical cells in the peripheral blood even in the absence of an increased lymphocytosis.
Article
Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearrangement and cyclin D1 gene overexpression. Some aggressive variants of MCL have been described with blastic or large cell morphology, higher proliferative activity, and shorter survival. The cyclin-dependent kinase inhibitors (CDKIs) p21Waf1 and p16INK4a have been suggested as candidates for tumor-suppressor genes. To determine the role of p21Waf1 and p16INK4a gene alterations in MCLs, we examined the expression, deletions, and mutations of these genes in a series of 24 MCLs, 18 typical, and 6 aggressive variants. Loss of expression and/or deletions of p21Waf1 and p16INK4a genes were detected in 4 (67%) aggressive MCLs but in none of the typical variants. Two aggressive MCLs showed a loss of p16INK4a expression. These cases showed homozygous deletions of p16INK4a gene by Southern blot analysis. An additional aggressive MCL in which expression could not be examined showed a hemizygous 9p12 deletion. Loss of p21Waf1 expression at both protein and mRNA levels was detected in an additional aggressive MCL. No p21Waf1 gene deletions or mutations were found in this case. The p21Waf1 expression in MCLs was independent of p53 mutations. The two cases with p53 mutations showed p21Waf1 and p16INK4a expression whereas the 4 aggressive MCLs with p16INK4a and p21Waf1 gene alterations had a wild-type p53. p21Waf1 and p16INK4a were expressed at mRNA and protein levels in all typical MCLs examined. No gene deletions or point mutations were found in typical variants. Two typical MCLs showed an anomalous single-stranded conformation polymorphism corresponding to the known polymorphisms at codon 148 of p16INK4a gene and codon 31 of p21Waf1 gene. These findings indicate that p21Waf1 and p16INK4a alterations are rare in typical MCLs but the loss of p21Waf1 and p16INK4a expression, and deletions of p16INK4a gene are associated with aggressive variants of MCLs, and they occur in a subset of tumors with a wild-type p53 gene.
Article
Sixty-four cases of mantle cell (centrocytic) non-Hodgkin's lymphomas have been analyzed for their cytomorphologic features, proliferation indices, bcl-1 rearrangements, p53 expression patterns, and DNA content by both interphase cytogenetic and DNA flow cytometric analyses. According to cytomorphology, three subtypes were recognized: a common, a lymphoblastoid, and a pleomorphic variant of mantle cell lymphoma (MCL). Blastoid MCL subtypes were characterized by distinctly elevated mitotic counts (57 and 51/10 HPF v 21/10 high-power fields in common MCL), proliferation indices (58% and 53% v 27% in common types, respectively; P < .001), frequent bcl-1 rearrangements at the major translocation cluster locus (59% v 40%), and overexpression of p53 (21% v 6%). However, the most interesting finding was a striking tendency of blastoid MCL subtypes to harbor chromosome numbers in the tetraploid range (36% of lymphoblastoid and 80% of pleomorphic types v 8% of common variants, P < .001), a feature clearly separating these neoplasms from other types of B-cell non-Hodgkin's lymphoma and possibly being related to cyclin D1 overexpression. Our data indicate that, although characterized by a uniform immunophenotype and common biologic background, MCL shows a broad spectrum of morphologic features ranging from small cell to blastoid types and that the morphologic spectrum is mirrored by distinct biologic features.
Article
Mantle cell lymphoma (MCL) is a relatively uncommon yet distinct type of malignant lymphoma whose clinical and pathological characterization has been limited by the small numbers of cases published to date. We studied 80 cases of MCL seen at a single institution over 7 years to determine both clinical and pathological prognostic factors. The patients in this study were predominantly male (70%) and older (mean age, 63 years) and presented with advanced-stage disease (88%). Extranodal involvement was common. Median overall survival (OS) was 43 months. Except for performance status, prognosis was not significantly influenced by clinical prognostic factors. Histologically, MCL architecture was classified as diffuse (78%), nodular (16%), or mantle zone (6%); the OS among these groups was identical. Increased mitotic activity (>20 mitotic figures per 10 high power fields), blastic transformation, and peripheral blood involvement at diagnosis also predicted for a worse outcome, but bone marrow involvement did not. The presence or absence of a translocation t(11; 14) by cytogenetic analysis or a bcl-1 rearrangement by Southern analysis did not significantly predict outcome. In summary, this study of 80 cases of MCL highlights its distinctive clinicopathologic features and shows that increased mitotic activity, blastic morphology, and peripheral blood involvement at diagnosis are prognostically important factors.
Article
Clinical data and histologic material were retrospectively analyzed in 46 cases of previously untreated mantle cell lymphoma (MCL) to more fully characterize the clinical response pattern of these lymphomas and to determine whether growth pattern significantly affected clinical outcome. The histologic pattern was classified as diffuse (61%), nodular (13%), and mantle zone (26%) in accordance with stated criteria. Bone marrow infiltration was detected in 69% of cases; the frequency of involvement correlated with histologic pattern, being most common in diffuse variants and least common in mantle zone variants. Other sites of extranodal involvement were observed in 50% of cases. Cyclin-D1 staining revealed nuclear positivity in 23 of 25 patients (92%) and no difference was observed between the various histologic patterns. Rearrangement at the bcl-1 major translocation cluster (MTC) was detected in seven of 21 cases, without regard for histologic pattern. Complete response rates to doxorubicin-based regimens showed a striking correlation with histologic pattern. Seventy-three percent of patients with a mantle zone pattern attained a complete response compared with only 25% of patients with a nodular pattern and 19% with a diffuse pattern. Three-year survival rates were 100%, 50%, and 55% for patients with mantle zone, nodular, and diffuse histologic patterns, respectively. We conclude that (1) diffuse and nodular MCL are associated with a poor treatment response and a poor overall survival rate; (2) the mantle zone variant exhibits the clinical attributes of a low-grade lymphoma; and (3) the poor survival rates of patients with nodular and diffuse MCL suggest that these variants be classified as intermediate-grade lymphomas. However, the trend of the time to treatment failure curve does not indicate that current regimens can cure MCL.
Article
Mantle-cell lymphoma (MCL) is characterized by overexpression of the G1 cyclin, cyclin D1, strongly implicating this cell-cycle regulatory element in MCL pathogenesis. Recently, loss-of-function mutations in cell-cycle negative regulatory elements, including p53 point mutations and deletions of the cyclin-dependent kinase inhibitors (CDKI) p15 and p16 have been described in a subset of MCLs and have been associated with aggressive clinical course, blastic morphology, and extranodal dissemination. The objective of the present study was to analyze two newly identified members of the p16 (INK4A; MTS1) CDKI family, p18 and p19, in MCL. Such analyses have not been previously reported. DNA was isolated from tissue biopsies, peripheral blood cells, or bone marrow cells of 45 patients with MCL and 15 with chronic lymphocytic leukemia (CLL). Southern blot analysis was performed with p18 and p19 probes and compared to placental control DNA and to control probe hybridizations for evidence of p18 or p19 gene deletion or rearrangement. P18 deletion was identified in one MCL but in no case of CLL. One MCL sample had rearrangement of the p18 gene; this case also had coexisting homozygous p15 and p16 deletion. Both cases with p18 abnormalities had blastic morphology, and one had extranodal disease with renal parenchymal invasion. P18 rearrangement or deletion as detected by Southern blot is a rare event in MCL, but may be associated with blastic morphology. P53 mutations and deletions of the CDKI p15 and p16 appear to be more frequent in MCL, although further studies are necessary to assess the presence of inactivating point mutations or altered expression of p16 family proteins.
Article
Mantle cell lymphoma (MCL) has recently become generally accepted as a subentity of malignant lymphomas that is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in the overexpression of cyclin D1. Cyclin D1 forms a complex with cell cycle-dependent kinase (cdk) 4, which inactivates the retinoblastoma protein (pRB) via phosphorylation. However, in transgenic mice, the overexpression of cyclin D1 alone is not sufficient for the development of malignant lymphoma. To determine whether other members of the pRB pathway contribute to the malignant transformation of MCL, we analyzed 37 cases of MCL that were well characterized by morphology, immunophenotype, and/or interphase cytogenetics [detection of t(11;14)(q13;q32)]. Interphase fluorescence in situ hybridization was performed using a cosmid contig (250 kb) of the CDKN2/p16 region (encoding an inhibitor of the cyclin D1/cdk4 complex) and a phage contig (200 kb) of the Rb region. CDKN2/p16 deletion was detected in 15 cases (41%), including 6 homozygous deletions; Rb was deleted in 15 cases (41%), all of which were hemizygous deletions. Nine cases (24%) had deletions of both CDKN2/p16 and Rb. Further analysis of a subset of 17 MCLs revealed a highly significant correlation between CDKN2/p16 deletion and proliferation index, determined by the rate of Ki67 expression (P = 0.014; t test). No significant correlation was found between CDKN2/p16 deletion and the blastoid variant of MCL (P = 0.23; Fisher's test) or between proliferation index and blastoid morphology (P = 0.51; t test). Deletion of Rb did not have any impact on cell proliferation in addition to CDKN2/p16 deletion (P = 0.76; t test). Additional analysis of 13q14 deletions suggests that these deletions may target another gene telomeric to Rb. We conclude that deletion of CDKN2/p16 occurs in approximately one-half of MCLs and is a more relevant indicator of the proliferative features as compared to morphological criteria. In contrast, although deletions of chromosomal band 13q14 are frequent in MCL, inactivation of Rb seems not to be involved in the pathogenesis of MCL.
Article
The goal of this study was to analyze the presenting features, natural history, and prognostic factors in 59 patients with well characterized mantle cell lymphoma (MCL). Cases were classified as nodular or diffuse and as typical or blastic variants. Age, performance status (PS), histologic variants, mitotic index (MI), hematologic parameters, tumor extension data, and International Prognostic Index (IPI) were recorded and evaluated for prognosis. The median age of the patients was 63 years (range, 39-83 years), and the male to female ratio was 3:1. Fifty-three patients had typical histology (3 nodular and 50 diffuse), and 6 had the blastic variant. Approximately 95% of patients presented with advanced stage disease (Ann Arbor Stage III-IV). Leukemic expression was observed in 58%. Complete and partial response rates were 19% and 46%, respectively. Parameters associated with lower response rate were Stage IV, high/intermediate or high risk IPI, and increased lactate dehydrogenase (LDH) level. In the logistic regression analysis, high LDH level and Stage IV disease were associated independently with lower response rate. Median survival was 49 months. Parameters associated with a short survival were: poor PS, splenomegaly, B-symptoms, MI > 2.5, leukocyte count > 10 x 10(9)/L, high LDH level, blastic variant, and high/intermediate or high risk IPI. In the Cox proportional hazards regression model, only poor PS (relative risk [RR] = 3.3; P = 0.002), splenomegaly (RR = 2.8; P = 0.007), and MI > 2.5 (RR = 2.4; P = 0.012) were associated with short survival. In this series, patients with MCL presented with advanced stage and extranodal involvement. Only a minority of patients achieved a complete response. The median survival was 4 years, with PS, splenomegaly, and MI being the most important factors predicting survival. These results show clearly that more effective therapies for MCL are needed.
Article
Two cases of mantle cell lymphoma with a unique CD8+ phenotype are reported. Both patients had disease that was resistant to therapy; one patient had the blastic variant of mantle cell lymphoma. Flow cytometric analysis of bone marrow and cerebrospinal fluid samples revealed a phenotype consistent with mantle cell lymphoma, with the additional finding of CD8 positivity in 40% or more of the tumor cells in both cases. This is the first description of such a finding, and CD8+ mantle cell lymphoma may represent a unique type of B-cell neoplasia. Our findings may be important in the prediction of therapeutic response or in the detection of residual disease after therapy.