Publications (60)261.27 Total impact
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Article: Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.
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ABSTRACT: Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.Journal of Experimental Medicine 08/2012; 209(9):1553-65. · 13.85 Impact Factor -
Article: Concomitant BCR-ABL1 translocation and JAK2(V617F) mutation in three patients with myeloproliferative neoplasms.
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ABSTRACT: Chronic myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells, which fall into distinct categories based on a number of characteristics including the presence of the BCR-ABL1 gene fusion (chronic myelogenous leukemia) or the JAK2(V617F) mutation (polycythemia vera, primary myelofibrosis, and essential thrombocythemia). One of the criteria in the 2008 World Health Organization Classification divides MPN into different categories based on the presence of an underlying genetic abnormality, however the WHO does not currently address the classification of myeloproliferative neoplasms that have more than one genetic abnormality. The coexistence of a JAK2(V617F) mutation and BCR-ABL1 is rare, and to our knowledge, less than 25 cases have been reported in the literature. Our case series examines the clinical, histopathologic, and genetic features of 3 patients with myeloproliferative neoplasms characterized by concomitant BCR-ABL1 and JAK2(V617F). The implications for diagnosis and treatment of patients with concomitant BCR-ABL1 and JAK2(V617F) are discussed as well as how the BCR-ABL1 and JAK2(V617F)-positive clones may be related to one another.Diagnostic molecular pathology: the American journal of surgical pathology, part B 07/2012; 21(3):176-83. · 1.58 Impact Factor -
Article: The B7 homologues and their receptors in hematologic malignancies.
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ABSTRACT: The B7 homologues and their receptors regulate both peripheral tolerance and adaptive immunity. This field is rapidly evolving as new ligands and receptors are being identified. Much of the work supporting their role in the regulation of host anti-tumor immunity has been derived from experimental models and clinical trials in solid malignancies. However, a growing body of evidence demonstrates that the B7-H family has important immunologic and non-immunologic functions in a variety of hematologic malignancies. Herein, we will review recent evidence that supports the therapeutic targeting of the B7 homologues in hematologic malignancies.European Journal Of Haematology 02/2012; 88(6):465-75. · 2.61 Impact Factor -
Article: Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies.
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ABSTRACT: Current pathologic criteria cannot reliably distinguish cutaneous anaplastic large cell lymphoma from other CD30-positive T-cell lymphoproliferative disorders (lymphomatoid papulosis, systemic anaplastic large cell lymphoma with skin involvement, and transformed mycosis fungoides). We previously reported IRF4 (interferon regulatory factor-4) translocations in cutaneous anaplastic large cell lymphomas. Here, we investigated the clinical utility of detecting IRF4 translocations in skin biopsies. We performed fluorescence in situ hybridization (FISH) for IRF4 in 204 biopsies involved by T-cell lymphoproliferative disorders from 182 patients at three institutions. In all, 9 of 45 (20%) cutaneous anaplastic large cell lymphomas and 1 of 32 (3%) cases of lymphomatoid papulosis with informative results demonstrated an IRF4 translocation. Remaining informative cases were negative for a translocation (7 systemic anaplastic large cell lymphomas; 44 cases of mycosis fungoides/Sézary syndrome (13 transformed); 24 peripheral T-cell lymphomas, not otherwise specified; 12 CD4-positive small/medium-sized pleomorphic T-cell lymphomas; 5 extranodal NK/T-cell lymphomas, nasal type; 4 gamma-delta T-cell lymphomas; and 5 other uncommon T-cell lymphoproliferative disorders). Among all cutaneous T-cell lymphoproliferative disorders, FISH for IRF4 had a specificity and positive predictive value for cutaneous anaplastic large cell lymphoma of 99 and 90%, respectively (P=0.00002, Fisher's exact test). Among anaplastic large cell lymphomas, lymphomatoid papulosis, and transformed mycosis fungoides, specificity and positive predictive value were 98 and 90%, respectively (P=0.005). FISH abnormalities other than translocations and IRF4 protein expression were seen in 13 and 65% of cases, respectively, but were nonspecific with regard to T-cell lymphoproliferative disorder subtype. Our findings support the clinical utility of FISH for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders in skin biopsies, with detection of a translocation favoring cutaneous anaplastic large cell lymphoma. Like all FISH studies, IRF4 testing must be interpreted in the context of morphology, phenotype, and clinical features.Modern Pathology 12/2010; 24(4):596-605. · 4.79 Impact Factor -
Chapter: Proteomics of Human Malignant Lymphoma
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ABSTRACT: The proteome represents the total complement of proteins present in a complex, an organelle, a cell, tissue, or an organism. Proteomics encompass the multifaceted study of protein expression, interactions, posttranslational modification, and function at the cellular level. Mass spectrometry offers significant opportunities for the analysis of single proteins and the unbiased large-scale analysis of proteins in complex mixtures. The ability to conduct large-scale investigation of proteins in an unbiased fashion dramatically improves the opportunities for biological discovery and is relevant for the elucidation of novel biological insights into physiology and disease. In this regard, mass spectrometry is considered a key technology that will drive the achievement of several milestones in the identification of key proteins involved in disease detection and treatment. This chapter provides a synopsis of the principles of the techniques employed in the current state-of-the art proteomics and the opportunities that this suite of technologies offers in biological discovery as it relates to human lymphomas. Advances in mass spectrometry-based proteomics have shifted the paradigm of translational cancer research (for a review of background on proteomics and mass spectrometry see). The achievement of the ultimate goals of identifying biomarkers for diagnosis and prognosis and the development of novel agents for therapy will require significant effort in understanding the basic protein building blocks and the global proteomic circuitry.12/2009: pages 191-202; -
Chapter: New Therapeutic Frontiers for Childhood Non-Hodgkin Lymphoma
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ABSTRACT: Childhood non-Hodgkin lymphoma (NHL) accounts for approximately 6 to 7% of all childhood cancers diagnosed below the age of 15 in the United States and consists of four major histological subtypes of both intermediate and high-grade NHL including Burkitt lymphoma (BL), lymphoblastic lymphoma (LL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL) (Cairo et al. 2005). While there are a large number of other histological subtypes of NHL that may occur in children, they only account for <5% of all cases of NHL diagnosed in the United States and Western Europe. Posttransplant lymphoproliferative disease (PTLD) may also occur in children following either solid organ transplantation or mismatched or T-cell depleted allogeneic stem cell transplantation and will be the subject of a separate chapter in this monograph. We will focus our discussion on the four major histological subtypes that account for >95% of all NHL in children (Cairo et al. 2005; Pinkerton 2005).12/2009: pages 177-213; -
Article: Expression of Grb2 distinguishes classical Hodgkin lymphomas from primary mediastinal B-cell lymphomas and other diffuse large B-cell lymphomas.
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ABSTRACT: Growth factor receptor-bound protein 2 is an adaptor molecule that mediates B-cell receptor (BCR) signaling pathways, but the expression of growth factor receptor-bound protein 2 in lymphoma tissues has not been reported. We sought to characterize growth factor receptor-bound protein 2 protein expression in reactive tonsillar tissues and lymphoma tissues obtained from diagnostic biopsies of classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and 20 low-grade B-cell lymphomas. Growth factor receptor-bound protein 2 expression was assessed in tissues by immunohistochemistry and in lymphoma cell lines by immunoblotting. In reactive lymphoid tissues, growth factor receptor-bound protein 2 was expressed in the cytoplasm of B-cells and histiocytes but not T-cells. Strong, cytoplasmic growth factor receptor-bound protein 2 expression was seen in the neoplastic cells of follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, splenic marginal zone lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, and nodular lymphocyte predominant Hodgkin lymphoma. In contrast, only 10% of the classical Hodgkin lymphomas showed growth factor receptor-bound protein 2 expression in the neoplastic cells. Growth factor receptor-bound protein 2 protein expression was detected by Western blotting in all lymphoma cell lines tested with higher levels in primary mediastinal large B-cell lymphoma compared with classical Hodgkin lymphoma cell lines. These findings support a role for growth factor receptor-bound protein 2 in the diagnostically challenging workup of classical Hodgkin lymphoma versus primary mediastinal large B-cell lymphoma and warrant further studies to evaluate the biologic significance of growth factor receptor-bound protein 2 in the pathogenesis of classical Hodgkin lymphoma.Human pathology 09/2009; 40(12):1731-7. · 3.03 Impact Factor -
Article: Immunomodulator agent-related lymphoproliferative disorders.
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ABSTRACT: The recent development of inhibitors of key immune response proteins has revolutionized the therapy of autoimmune diseases; these immunomodulator agents include monoclonal antibodies and receptor antagonists. However, as with all therapies, these new agents are not without side effects and complications. In particular, anti-tumor necrosis factor alpha (TNFalpha) agents have been reported to be associated with an increased incidence of lymphoproliferative disorders, infections, and vasculitis. We evaluated the clinicopathological features of 18 cases of immunomodulator agent-related lymphoproliferative disorders (IAR-LPD) from several institutions. These included 6 cases of B-cell lymphoma, 2 cases of T-cell lymphoma, 3 cases of classical Hodgkin lymphoma, and 7 atypical lymphoid proliferations that did not fulfill diagnostic criteria for lymphoma; two of the latter regressed after discontinuation of the immunomodulator agent therapy. All eight lymphoma patients with available information had also received prior chemotherapy (methotrexate or 6-mercaptopurine). EBV was strongly associated with the B-cell and classical Hodgkin lymphomas. This case series illustrates that a broad range of lymphoid proliferations can occur after immunomodulator agent therapy and that these immunomodulator agent-related lymphoproliferative disorders have considerable overlap with other well-defined lymphoproliferative diseases associated with iatrogenic immunosuppression. Further study is warranted to evaluate how these therapies interact with other immunosuppressive agents and the underlying abnormal immune system to enhance the development of lymphomas and atypical lymphoid proliferations.Modern Pathology 09/2009; 22(12):1532-40. · 4.79 Impact Factor -
Article: Commentary on the WHO 2008 classification of neoplasms arising from histiocytic and other accessory cells.
Journal of Hematopathology 08/2009; 2(2):75-76. -
Article: The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways.
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ABSTRACT: Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p32;q35) is a key oncogenic event in the pathogenesis of most anaplastic large cell lymphomas (ALCLs). The proteomic network alterations produced by this aberration remain largely uncharacterized. Using a mass spectrometry (MS)-driven approach to identify changes in protein expression caused by the NPM/ALK fusion, we identified diverse NPM/ALK-induced changes affecting cell proliferation, ribosome synthesis, survival, apoptosis evasion, angiogenesis, and cytoarchitectural organization. MS-based findings were confirmed using Western blotting and/or immunostaining of NPM/ALK-transfected cells and ALK-deregulated lymphomas. A subset of the proteins distinguished NPM/ALK-positive ALCLs from NPM/ALK-negative ALCLs and Hodgkin lymphoma. The multiple NPM/ALK-deregulated pathways identified by MS analysis also predicted novel biologic effects of NPM/ALK expression. In this regard, we showed loss of cell adhesion as a consequence of NPM/ALK expression in a kinase-dependent manner, and sensitivity of NPM/ALK-positive ALCLs to inhibition of the RAS, p42/44ERK, and FRAP/mTOR signaling pathways. These findings reveal that the NPM/ALK alteration affects diverse cellular pathways, and provide novel insights into NPM/ALK-positive ALCL pathobiology. Our studies carry important implications for the use of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers, and pathogenetically relevant therapeutic targets.Blood 07/2009; 114(8):1585-95. · 9.90 Impact Factor -
Article: Unraveling ALK signaling through phosphoproteomics.
Blood 04/2009; 113(12):2615-6. · 9.90 Impact Factor -
Article: P38 mitogen activated protein kinase expression and regulation by interleukin-4 in human B cell non-Hodgkin lymphomas.
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ABSTRACT: The prevalence and regulation of p38 mitogen activated protein kinase (MAPK) expression in human lymphomas have not been extensively studied. In order to elucidate the role of p38 MAPK in lymphomagenesis, we examined the expression of native and phosphorylated p38 (p-p38) MAPK in cell lines derived from human hematopoietic neoplasms including B cell lymphoma-derived cell lines using Western blot analysis. The p-p38 MAPK protein was also analyzed in 30 B cell non-Hodgkin lymphoma (NHL) tissue biopsies by immunohistochemistry. Our results show that the expression of p38 MAPK was up-regulated in most of the cell lines as compared with peripheral blood lymphocytes, while the expression of p-p38 MAPK was more variable. A subset of B cell NHL biopsies showed increased expression of p-p38 MAPK relative to reactive germinal center cells. Interleukin-4 (IL-4) induced a dose-dependent increase in the expression of p-p38 MAPK (1.6- to 2.8-fold) in cell lines derived from activated B cell-like diffuse large B cell lymphoma (DLBCL) but not those from germinal center-like DLBCL. No change was seen in native p38 MAPK. The in vitro kinase activity of p38 MAPK, however, was induced (1.6- to 3.2-fold) in all five cell lines by IL-4. Quantitative fluorescent RT-PCR demonstrated that all four isoforms of p38 MAPK gene were expressed in the lymphoma cell lines, with p38gamma and p38beta isoforms being predominant. IL-4 stimulation increased the expression of beta, gamma, and delta isoforms but not alpha isoform in two cell lines. In conclusion, there is constitutive expression and activation of p38 MAPK in a large number of B-lymphoma-derived cell lines and primary lymphoma tissues, supportive of its role in lymphomagenesis. The differential IL-4 regulation of p38 MAPK expression in cell lines derived from DLBCL may relate to the cellular origin of these neoplasms. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12308-009-0049-5) contains supplementary material, which is available to authorized users.Journal of Hematopathology 01/2009; 2(4):195-204. -
Article: Quantitative proteomic analysis of follicular lymphoma cells in response to rituximab.
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ABSTRACT: Rituximab is a monoclonal antibody that targets the uniquely expressed B-cell CD20 receptor. Although recently approved for treatment of follicular lymphomas, the intracellular events that occur when rituximab binds to CD20 are largely unknown. Quantitative proteomic analysis of B-cell lymphoma-derived cells exposed to rituximab was performed. Differentially expressed proteins belonged to functional groups involved in migration, adhesion, calcium-induced signaling, ubiquitination, and components of the phosphoinositol and NF-kappaB pathways. Our studies reveal the proteomic consequences of rituximab treatment and provide novel insights into the mechanism of action of the drug in susceptible B-cell lymphoproliferative disorders.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 11/2008; 877(13):1335-43. · 2.78 Impact Factor -
Article: Recurrent squamous cell carcinoma and follicular lymphoma arising in the scalp after treatment for lymphoma.
Pathology 05/2008; 40(3):316-20. · 2.38 Impact Factor -
Article: Analysis of gene expression profile of TPM3-ALK positive anaplastic large cell lymphoma reveals overlapping and unique patterns with that of NPM-ALK positive anaplastic large cell lymphoma.
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ABSTRACT: Anaplastic large cell lymphoma (ALCL) comprises a group of non-Hodgkin lymphomas characterized by the expression of the CD30/Ki-1 antigen. A subset of ALCL is characterized by chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2. While the most common translocation is the t(2;5)(p23;q35) involving the nucleophosmin (NPM) gene on chromosome 5, up to 12 other translocations partners of the ALK gene have been identified. One of these is the t(1;2)(q25;p23) which results in the formation of the chimeric protein TPM3-ALK. While several of the signaling pathways induced by NPM-ALK have been elucidated, those involved in ALCLs harboring TPM3-ALK are largely unknown. In order to investigate the expression profiles of ALCLs carrying the NPM-ALK and TPM3-ALK fusions, we carried out cDNA microarray analysis of two ALCL tissue samples, one expressing the NPM-ALK fusion protein and the other the TPM3-ALK fusion protein. RNA was extracted from snap-frozen tissues, labeled with fluorescent dyes and analyzed using cDNAs microarray containing approximately 9,200 genes and expressed sequence tags (ESTs). Quantitative fluorescence RT-PCR was performed to validate the cDNA microarray data on nine selected gene targets. Our results show a significant overlap of genes deregulated in the NPM-ALK and TPM-ALK positive lymphomas. These deregulated genes are involved in diverse cellular functions, such as cell cycle regulation, apoptosis, proliferation, and adhesion. Interestingly, a subset of the genes was distinct in their expression pattern in the two types of lymphomas. More importantly, many genes that were not previously associated with ALK positive lymphomas were identified. Our results demonstrate the overlapping and unique transcriptional patterns associated with the NPM-ALK and TPM3-ALK fusions in ALCL.Leukemia Research 04/2008; 32(3):383-93. · 2.92 Impact Factor -
Article: Chronic myeloid leukemia as a secondary malignancy after ALK-positive anaplastic large cell lymphoma.
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ABSTRACT: The development of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the adolescent population is very rare. CML occurring as a secondary malignancy in individuals treated for anaplastic large cell lymphoma (ALCL) is also rare. We present the case of a 16-year-old adolescent boy who developed a right orbital mass that was diagnosed as ALCL with the t(2;5)(p23;q25) chromosomal aberration. Four years after receiving treatment for ALCL, he presented with a swollen leg and a white cell count of 431,000. Peripheral blood and bone marrow evaluation revealed a myeloproliferative disorder. Cytogenetic and molecular studies demonstrated the presence of t(9;22). We present the histopathologic, molecular, and cytogenetic findings of this patient's initial presentation with systemic ALCL as well as his secondary presentation with CML 4 years later. Therapy-related CML and non-therapy-related secondary CML are discussed as potential explanations of this highly unusual clinical presentation.Human Pathlogy 11/2007; 38(10):1576-80. · 2.88 Impact Factor -
Article: Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed-Sternberg cells by LC-MS/MS.
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ABSTRACT: Mass spectrometry-based proteomics in conjunction with liquid chromatography and bioinformatics analysis provides a highly sensitive and high-throughput approach for the identification of proteins. Hodgkin lymphoma is a form of malignant lymphoma characterized by the proliferation of Reed-Sternberg cells and background reactive lymphocytes. Comprehensive analysis of proteins expressed and released by Reed-Sternberg cells would assist in the discovery of potential biomarkers and improve our understanding of its pathogenesis. The subcellular proteome of the three cellular compartments from L428 and KMH2 Hodgkin lymphoma-derived cell lines were fractionated, and analyzed by reverse-phase liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Additionally, proteins released by Hodgkin lymphoma-derived L428 cells were extracted from serum-free culture media and analyzed. Peptide spectra were analyzed using TurboSEQUEST against the UniProt protein database (5.26.05; 188 712 entries). A subset of the identified proteins was validated by Western blot analysis, immunofluorescence microscopy and immunohistochemistry. A total of 1945 proteins were identified with 785 from the cytosolic fraction, 305 from the membrane fraction, 441 from the nuclear fraction and 414 released proteins using a minimum of two peptide identifications per protein and an error rate of <5.0%. Identification of proteins from diverse functional groups reflected the functional complexity of the Reed-Sternberg proteome. Proteins with previously reported oncogenic function in other cancers and from signaling pathways implicated in Hodgkin lymphoma were identified. Selected proteins without previously demonstrated expression in Hodgkin lymphoma were validated by Western blot analysis (B-RAF, Erb-B3), immunofluorescence microscopy (Axin1, Tenascin-X, Mucin-2) and immunohistochemistry using a tissue microarray (BRAF, PIM1). This study represents the first comprehensive inventory of proteins expressed by Reed-Sternberg cells of Hodgkin lymphoma and demonstrates the utility of combining cellular subfractionation, protein precipitation, tandem mass spectrometry and bioinformatics analysis for comprehensive identification of proteins that may represent potential biomarkers of the disease.Laboratory Investigation 11/2007; 87(11):1113-24. · 3.64 Impact Factor -
Article: NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma.
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ABSTRACT: Anaplastic large-cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35), resulting in aberrant expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). We show that in 293T and Jurkat cells, forced expression of active NPM-ALK, but not kinase-dead mutant NPM-ALK (210K>R), induced JNK and cJun phosphorylation, and this was linked to a dramatic increase in AP-1 transcriptional activity. Conversely, inhibition of ALK activity in NPM-ALK(+) ALCL cells resulted in a concentration-dependent dephosphorylation of JNK and cJun and decreased AP-1 DNA-binding. In addition, JNK physically binds NPM-ALK and is highly activated in cultured and primary NPM-ALK(+) ALCL cells. cJun phosphorylation in NPM-ALK(+) ALCL cells is mediated by JNKs, as shown by selective knocking down of JNK1 and JNK2 genes using siRNA. Inhibition of JNK activity using SP600125 decreased cJun phosphorylation and AP-1 transcriptional activity and this was associated with decreased cell proliferation and G2/M cell-cycle arrest in a dose-dependent manner. Silencing of the cJun gene by siRNA led to a decreased S-phase cell-cycle fraction associated with upregulation of p21 and downregulation of cyclin D3 and cyclin A. Taken together, these findings reveal a novel function of NPM-ALK, phosphorylation and activation of JNK and cJun, which may contribute to uncontrolled cell-cycle progression and oncogenesis.Blood 09/2007; 110(5):1621-30. · 9.90 Impact Factor -
Article: Proteome-wide changes induced by the Hsp90 inhibitor, geldanamycin in anaplastic large cell lymphoma cells.
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ABSTRACT: The molecular chaperone heat shock protein 90 (Hsp90) affects the function of many oncogenic signaling proteins including nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressed in anaplastic large cell lymphoma (ALCL). While ALK-positive ALCL cells are sensitive to the Hsp90 inhibitor and the geldanamycin (GA) analog, 17-allylamino-17-demethoxygeldanamycin (17-AAG), the proteomic effects of these drugs on ALK-positive ALCL cells are unpublished. In this study, we investigated the cellular, biologic, and proteomic changes occurring in ALK-positive ALCL cells in response to GA treatment. GA induced G2/M cell cycle arrest and caspase-3-mediated apoptosis. Furthermore, quantitative proteomic changes analyzed by cleavable isotope-coded affinity tag-LC-MS/MS (cICAT-LC-MS/MS) identified 176 differentially expressed proteins. Out of these, 49 were upregulated 1.5-fold or greater and 70 were downregulated 1.5-fold or greater in GA-treated cells. Analysis of biological functions of differentially expressed proteins revealed diverse changes, including induction of proteins involved in the 26S proteasome as well as downregulation of proteins involved in signal transduction and protein and nucleic acid metabolism. Pathway analysis revealed changes in MAPK, WNT, NF-kappaB, TGFbeta, PPAR, and integrin signaling components. Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in ALK-positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects.PROTEOMICS 09/2007; 7(15):2603-16. · 4.51 Impact Factor -
Article: Global proteome profiling of NPM/ALK-positive anaplastic large cell lymphoma.
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ABSTRACT: Constitutive overexpression of nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) is a key oncogenic event in anaplastic large cell lymphomas (ALCL) that carry the t(2;5)(p23;q35) translocation. Global proteomic analysis of NPM/ALK-positive ALCL would improve understanding of the disease pathogenesis and yield new candidate targets for novel treatment and diagnostic strategies. To comprehensively determine the inventory of proteins from NPM/ALK-positive ALCL SUDHL-1 cells, the membrane, cytoplasm, and nuclear subcellular fractions were resolved by one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The MS spectra were interpreted using SEQUEST to search the electronic UniProt protein database, and analyzed by ProteinProphet and INTERACT. A total of 623 proteins consisting of 210 membrane, 229 cytoplasm, and 184 nuclear proteins were identified with a <or=5% error rate. Extensive annotation and systematic examination of the literature for information on 209 representative proteins indicated that 19.9% were reported to be expressed in T cells and 44.7% were reported to have important function in cancers, while only 4.3% were reported to be involved in ALCL pathogenesis. Categorization of proteins into functional groups was performed using GOMiner. A subset of the identified proteins was confirmed by Western blots and immunohistochemistry of tissue samples. We present an extensive catalog of proteins expressed by NPM/ALK-positive ALCL. This study illustrates the potential for novel pathogenetic discovery in NPM/ALK-positive ALCL and the utility of combining cellular subfractionation, 1D SDS-PAGE, and LC-MS/MS for the comprehensive protein analysis of lymphoma.Experimental Hematology 08/2007; 35(8):1240-8. · 2.90 Impact Factor
Top co-authors
Top Journals
Institutions
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2009–2012
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Concordia University–Ann Arbor
Ann Arbor, MI, USA -
University of Michigan
- Department of Pathology
Ann Arbor, MI, USA
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2002–2009
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University of Utah
- • Department of Pathology
- • Division of Rheumatology
Salt Lake City, UT, USA -
National Institutes of Health
- Laboratory of Pathology
Bethesda, MD, USA
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2008
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University of Washington Seattle
- Department of Pathology
Seattle, WA, USA
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2007
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Pennsylvania State University
- Department of Pathology
University Park, MD, USA
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2005
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The Ohio State University
- Pathology
Columbus, OH, USA
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2003
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University of Toronto
- Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
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