[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. Investigating mechanisms underlying acquired severe HDL deficiency in noncritically ill patients ("disappearing HDL syndrome") could provide new insights into HDL metabolism.
To determine the cause of low HDL-C in patients with severe acquired HDL deficiency.
METHODS AND RESULTS:
Patients with intravascular large B-cell lymphoma (n = 2), diffuse large B-cell lymphoma (n = 1), and autoimmune lymphoproliferative syndrome (n = 1) presenting with markedly decreased HDL-C, low low-density lipoprotein cholesterol (LDL-C), and elevated triglycerides were identified. The abnormal lipoprotein profile returned to normal after therapy in all 4 patients. All patients were found to have markedly elevated serum interleukin-10 (IL-10) levels that also normalized after therapy. In a cohort of autoimmune lymphoproliferative syndrome patients (n = 93), IL-10 showed a strong inverse correlation with HDL-C (R(2) = 0.3720, P < .0001). A direct causal role for increased serum IL-10 in inducing the observed changes in lipoproteins was established in a randomized, placebo-controlled clinical trial of recombinant human IL-10 in psoriatic arthritis patients (n = 18). Within a week of initiating subcutaneous recombinant human IL-10 injections, HDL-C precipitously decreased to near-undetectable levels. LDL-C also decreased by more than 50% (P < .0001) and triglycerides increased by approximately 2-fold (P < .005). All values returned to baseline after discontinuing IL-10 therapy.
Increased IL-10 causes severe HDL-C deficiency, low LDL-C, and elevated triglycerides. IL-10 is thus a potent modulator of lipoprotein levels, a potential new biomarker for B-cell disorders, and a novel cause of disappearing HDL syndrome
[Show abstract][Hide abstract] ABSTRACT: Purpose:
In contrast with the classic form, variant hairy cell leukemia (HCLv) responds poorly to single-agent purine analogs, expresses unmutated BRAF, has shorter overall survival, and lacks effective standard therapy. No treatment has achieved a high complete remission (CR) rate even in small series, and of 39 reported cases from six studies, overall response rate after cladribine was 44% with 8% CRs. Rituximab has been found to increase the sensitivity of malignant cells to cladribine, suggesting that combination with cladribine might improve response in HCLv. To test this hypothesis, patients with HCLv were treated with simultaneous cladribine and rituximab.
Patients with HCLv with 0 to 1 prior courses of cladribine received cladribine 0.15 mg/kg for days 1 to 5, with eight weekly doses of rituximab 375 mg/m(2) beginning day 1. Restaging was performed, and minimal residual disease (MRD) in blood and marrow was quantified using PCR, immunohistochemistry, and flow cytometry.
By 6 months, 9 (90%) of 10 patients achieved CR, compared with 3 (8%) of 39 reported cases treated with cladribine alone (P < 0.0001). Of the 9 CRs, 8 remain free of MRD at 12 to 48 (median 27) months of follow-up. No dose-limiting toxicities were observed when beginning cladribine and rituximab on the same day, although most patients required short-term steroids to prevent and treat rituximab infusion reactions. Cytopenias in CRs resolved in 7 to 211 (median 34) days without major infections.
Although cladribine alone lacks effectiveness for early or relapsed HCLv, cladribine with immediate rituximab achieves CRs without MRD and is feasible to administer.
Clinical Cancer Research 11/2013; 19(24). DOI:10.1158/1078-0432.CCR-13-1752 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ibrutinib (PCI-32765) is a highly potent, oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for the treatment of B cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B cell receptor (BCR) pathway. In a Phase I study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). We here characterize the patterns and phenotypes of cells mobilized among patients with MCL, and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38 and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40-60% after treatment. Mechanistically, ibrutinib inhibited BCR, and chemokine mediated adhesion and chemotaxis of MCL cell lines, and dose-dependently inhibited BCR, stromal cell and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in co-culture. We propose BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This study is registered at http://clinicaltrials.gov, identifier: NCT00114738.
[Show abstract][Hide abstract] ABSTRACT: Burkitt's lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies. The normal germinal centre B cell is the presumed cell of origin for both BL and diffuse large B-cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may use different oncogenic pathways. BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein-Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC, the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.
[Show abstract][Hide abstract] ABSTRACT: Survival of chronic lymphocytic leukemia (CLL) cells in vivo is supported by the tissue microenvironment, which includes components of the extracellular matrix. Interactions between tumor cells and the extracellular matrix are in part mediated by CD44, whose principal ligand is hyaluronic acid. Here, we show that CD44 is more highly expressed on CLL cells of the clinically more progressive immunglobulin heavy chain variable gene (IGHV)-unmutated subtype than on cells of the IGHV-mutated type. Engagement of CD44 activated the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK)/ERK pathways and increased myeloid cell leukemia sequence 1 (MCL-1) protein expression. Consistent with the induction of these anti-apoptotic mechanisms, CD44 protected CLL cells from spontaneous and fludarabine-induced apoptosis. Obatoclax, an antagonist of MCL-1, blocked the pro-survival effect of CD44. In addition, obatoclax synergized with fludarabine to induce apoptosis of CLL cells. In conclusion, components of the extracellular matrix may provide survival signals to CLL cells through engagement of CD44. Inhibition of MCL-1 is a promising strategy to reduce the anti-apoptotic effect of the microenvironment on CLL cells.
[Show abstract][Hide abstract] ABSTRACT: Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol.
[Show abstract][Hide abstract] ABSTRACT: Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a small modular immunopharmaceutical (CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the histone deacetylase inhibitor suberoylanilide hydroxamic acid in induction of the hypermethylated genes and anti-MCL cytotoxicity. Our data show prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.
[Show abstract][Hide abstract] ABSTRACT: The anti-CD52 antibody alemtuzumab has been explored as a novel targeted therapy in T cell malignancies. To assess the suitability of alemtuzumab therapy, we carried out a comprehensive study of CD52 expression using flow cytometry (FC) in 78 untreated patients diagnosed with mature T/natural killer (NK) cell neoplasms, including 34 adult T cell leukaemia/lymphomas (ATLL), two anaplastic large cell lymphomas (ALCL), three angioimmunoblastic T cell lymphomas (AITL), 16 cutaneous T cell lymphomas (CTCL), four extra-nodal T/NK cell lymphomas (ENT/NKCL), four hepatosplenic T cell lymphomas (HSTCL), 13 peripheral T cell lymphomas, not otherwise specified (PTCL-NOS) and two T-prolymphocytic leukaemia (T-PLL). The level of CD52 expression was quantified using QuantiBRITE standard beads. The level of CD52 expression varied widely within each diagnostic category. All AITL, HSTCL and T-PLL cases were CD52-positive and the frequency of CD52 expression was high in PTCL-NOS (92.3%), ATLL (94.1%) and CTCL (87.5%), implying a rational role for alemtuzumab in the treatment of these diseases; however, CD52 expression was low in ALCL (50%) and ENT/NKCL (25%). FC testing for cell surface expression of CD52 is indicated in patients with T/NK cell malignancies being considered for alemtuzumab therapy. Further studies are necessary to determine if the level of CD52 expression correlates with response to therapy.
British Journal of Haematology 03/2009; 145(2):173-9. DOI:10.1111/j.1365-2141.2009.07606.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peripheral T-cell lymphomas are uncommon lymphomas that show T-cell antigenic loss and clonal T-cell receptor (TCR) gene rearrangement. Rare cases of T-cell lymphomas with aberrant expression of CD20 have been described. However, CD19 coexpression in a mature T-cell neoplasm has not been reported.
Histology, immunohistochemistry (IHC), and PCR for TCR gene rearrangement were performed on an excised lymph node specimen and a subsequent fine needle aspiration (FNA) of an additional lymph node. Flow cytometry (FC) was performed on FNA and peripheral blood specimen.
The lymph node's architecture was effaced by a diffuse atypical lymphoid proliferation that, by IHC, was positive for CD3, CD2, and CD43 and negative for CD4, CD5, CD8, TdT, CD1a, and B-cell-associated antigens PAX-5, CD20, and CD79a. A clonal TCR gene rearrangement was detected. FC was performed on a subsequent FNA, and peripheral blood specimen demonstrated an aberrant T-cell population with expression of CD2, CD3, CD27, TCR alpha/beta, CD52, CD38, CD45, and CD26 (partial expression) and negative for CD4, CD5, CD7, CD8, CD10, CD30, and CD56. The aberrant T-cell population also expressed bright CD19.
Using FC, we describe the first case of peripheral T-cell lymphoma with aberrant coexpression of CD19.
Cytometry Part B Clinical Cytometry 03/2009; 76(2):142-9. DOI:10.1002/cyto.b.20442 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatosplenic (gammadelta) T-cell lymphoma (HSTCL) is an uncommon T-cell lymphoma with an aggressive clinical course and poor prognosis. Bone marrow and peripheral blood are frequently involved, with central nervous system involvement less common. We describe a case of a 31-year old man diagnosed with a gammadelta HSTCL in 2003, successfully treated with chemotherapy and allogeneic stem cell transplantation, and followed from 2003 to present. Four-color flow cytometry (FC) was performed on a BD FACSCalibur and data analyzed with CellQuest Pro and FCS Express software. For cerebrospinal fluid (CSF), all cells were acquired due to limited material. Cytological correlation was available on all specimens. Molecular studies for T-cell gene rearrangement were non-contributory. By FC, the diagnostic HSTCL immunophenotype was CD3 (+), CD7 (+), CD2 (+), CD5 (-), CD4 (-), CD8 (-), TCR gammadelta (+). Subsequent CSF FC analysis revealed a distinct population of gammadelta T-cells in all specimens, ranging from <1% to 13% of lymphocytes. Consistently, the gammadelta T-cells exhibited a different immunophenotypic profile from the reported diagnostic immunophenotype; they expressed CD5, and exhibited a heterogeneous pattern of CD8 expression. Comparison to in-house cases from patients with hairy cell leukemia and concomitant increases in non-neoplastic gammadelta T-cells was performed. The persistent gammadelta T-cells from the CSF of the patient with HSTCL were immunophenotypically consistent with non-neoplastic gammadelta T-cells. We describe an unusual case of persistent gammadelta T-cells in the CSF of a patient during 6 years of flow cytometric follow-up after treatment for gammadelta HSTCL. By cytology, non-neoplastic and malignant gammadelta T-cells are often difficult to distinguish. FC analysis helps to make this distinction, even with a limited panel. By FC, the gammadelta-T cells in the CSF of this patient are immunophenotypically consistent with non-neoplastic gammadelta T-cells. Remarkably, this finding is underscored by the patient's unusual clinical picture; he remains well and disease free.
International journal of clinical and experimental pathology 01/2009; 3(1):110-6. · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leptomeningeal disease is an important adverse complication occurring in patients with B and T cell lymphomas and acute leukemias of lymphoid and myeloid origin. Recent reports suggest that multiparameter flow cytometry immunophenotypic assessment of spinal fluid samples could improve the efficiency of detection of CNS involvement, due to its high specificity and greater sensitivity. However, spinal fluid samples are frequently paucicellular with a rapidly decreasing cell viability. Staining of spinal fluid therefore requires dedicated sample storage/transport, staining, and preparation protocols. The Basic Protocol in this unit outlines a consensus multiparameter (3- to 8-color) flow cytometry immunophenotypic protocol for the evaluation of CNS involvement of cerebrospinal fluid (CSF) samples by neoplastic cells. A Support Protocol describing the simultaneous assessment of surface and cytoplasmic antigens is also provided. Finally, in the Alternate Protocol, we describe a method to calculate absolute numbers of both normal and pathological cell subpopulations by adding counting beads to the assay.
Current protocols in cytometry / editorial board, J. Paul Robinson, managing editor ... [et al.] 08/2008; Chapter 6:Unit 6.25. DOI:10.1002/0471142956.cy0625s45
[Show abstract][Hide abstract] ABSTRACT: Familial chronic lymphocytic leukemia (CLL) has the most frequent familial aggregation among hematological malignancies. Familial CLL families have been studied to identify susceptibility genes and other factors that contribute in the etiology of CLL. To date no study has been conducted to evaluate and compare patterns of cell surface antigen expression in familial CLL and sporadic CLL.
The pattern of cell surface antigen expression was studied in familial and sporadic CLL to determine if unique identifiers of familial CLL could be detected. Survival in familial CLL verses sporadic CLL was compared and the association between prognosis and CD38 expression studied.
Familial and sporadic CLL demonstrated the same characteristic immunophenotype (positive for surface immunoglobulin, CD5, CD19, and CD23 with dim CD20, and CD22). CD2 and CD13 expression, however, were more frequent (30% of cases) in familial CLL (P = 0.0003 for CD2, P = 0.006 for CD13) than in sporadic CLL (2-6%). There was no significant difference in survival in the two groups studied. Although the incidence of CD38 expression was similar in familial and sporadic CLL (47% and 44% respectively) the association with prognosis differed. There was a trend to decreased survival in CD38 positive sporadic (P = 0.06) but not familial CLL patients.
We conclude that detection of CD2 or CD13 expression in CLL suggests familial CLL and examination of family history for additional affected members is warranted. Furthermore, CD38 expression does not carry the negative prognosis observed in sporadic CLL.
Cytometry Part B Clinical Cytometry 07/2008; 74(4):221-6. DOI:10.1002/cyto.b.20423 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoimmune lymphoproliferative syndrome (ALPS) is associated with mutations that impair the activity of lymphocyte apoptosis proteins, leading to chronic lymphadenopathy, hepatosplenomegaly, autoimmunity, and an increased risk of lymphoma. We investigated the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) in discriminating benign from malignant lymphadenopathy in ALPS. We report that FDG avidity of benign lymph nodes in ALPS can be high and, hence, by itself does not imply presence of lymphoma; but FDG-PET can help guide the decision for selecting which of many enlarged nodes in ALPS patients to biopsy when lymphoma is suspected.
American Journal of Hematology 02/2006; 81(2):81-5. DOI:10.1002/ajh.20523 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe chronic active Epstein-Barr virus disease (SCAEBV) is characterized by elevated EBV DNA levels in the blood and EBV DNA, RNA, or proteins in tissues with lymphocytic infiltration. Patients present with fever, adenopathy, and splenomegaly and complications include cytopenias, hepatitis, and neurological disorders. Most patients we studied developed progressive immunodeficiency and died of infections or progressive lymphoproliferation. We report here on two men with SCAEBV. The first presented with fever, pancytopenia, adenopathy, and splenomegaly, followed by hepatitis, neuropathy, encephalomyelitis, and uveitis. Lymph node and spleen showed abundant EBV RNA and hemophagocytosis. Treatment with corticosteroids and azathioprine controlled symptoms for several years, but he developed clonal T cell infiltration of the bone marrow and liver which progressed despite chemotherapy. After receiving a matched unrelated bone marrow transplant his disease resolved and he remains asymptomatic and with negative EBV serologies and viral load 5 years later. The second patient presented with recurrent fever, adenopathy, rash, followed by splenomegaly, uveitis and neuropathy. A lymph node biopsy showed a polymorphic EBV-positive B cell lymphoma, his skin showed abundant EBV RNA, and his blood EBV viral load was >106 genome copies/106 cells. He did not respond to interferon-α, rituximab, autologous EBV-specific cytotoxic lymphocytes, or chemotherapy. After allogeneic stem cell transplantation his viral load initially was undetectable, became markedly elevated at 6 weeks, and is now undetectable 5 months after transplant without EBV-related symptoms. Bone marrow or stem cell transplantation is likely curative for SCAEBV which otherwise has a relentless, fatal course.
Infectious Diseases Society of America 2005 Annual Meeting; 10/2005
[Show abstract][Hide abstract] ABSTRACT: In this study we compared clinical findings with flow cytometric immunophenotypic results in a series of patients with aggressive and indolent gamma delta T-cell malignancies with peripheral blood and/or bone marrow involvement.
Gamma delta T-cell malignancies were detected based on flow cytometric demonstration of an abnormal T-cell population staining positive with T-cell receptor gamma delta and confirmed by morphologic and clinical reviews. Clinical data were obtained through chart review and discussion with the patients' physicians.
Blood or bone marrow involvement was present in all patients. Hepatosplenic and cutaneous gamma delta T-cell lymphomas had an aggressive clinical course, whereas the gamma delta T-cell large granular lymphocyte (LGL) leukemias had an indolent course. Expressions of CD5, CD8, CD16, and CD57 differed in gamma delta T-cell LGL leukemia compared with hepatosplenic and cutaneous gamma delta T-cell lymphomas.
Gamma delta T-cell malignancies have a poor prognosis with the exception of gamma delta T-cell LGL leukemia (indolent process). Because CD57 expression is specific for gamma delta T-cell LGL leukemias, expression of this antigen may be associated with a more indolent clinical course. Because cutaneous gamma delta T-cell lymphoma can present with peripheral blood involvement, flow cytometric evaluation of peripheral blood is important in staging these patients.
Cytometry Part B Clinical Cytometry 09/2005; 67(1):6-12. DOI:10.1002/cyto.b.20063 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate potential immunotherapeutic strategies in B lymphocytic malignancies we looked for CTLs recognizing CD19 and CD20 epitopes.
Three CD19 and CD20 peptides binding to HLA-A*0201 were identified and used to detect peptide specific CTLs by a quantitative real-time PCR to measure IFN-gamma mRNA expression in 23 healthy individuals and 28 patients (18 chronic lymphocytic leukemia (CLL), 7 follicular lymphoma, 2 acute lymphocytic leukemia, and 1 large cell lymphoma). Peptide-specific CTLs were expanded in culture with CD40-activated B cells to test lytic activity in three patients.
In healthy individuals, CD8+ T-cell responses were detected in one to CD19(74-82), in three to CD20(127-135), and three to CD20(188-196). Seven of 27 patients (6 with CLL) had CD8+ T cells recognizing CD19(74-82). Seven patients responded to CD20(127-135) and three to CD20(188-196). All were CLL patients. CD19(74-82)-specific CTLs from three patients were expanded over 4 weeks. These cells were HLA-A*0201 specific and lytic for peptide-loaded antigen-presenting cells but not to malignant or unpulsed B cells.
CTLs that recognize CD19 and CD20 epitopes exist in healthy individuals and may be increased in CLL patients. They are of low avidity and require high doses of peptide for activation. Strategies to increase T-cell avidity would be necessary for T-cell immunotherapeutic approaches using the peptides studied.
Clinical Cancer Research 03/2004; 10(3):1047-56. DOI:10.1158/1078-0432.CCR-03-0075 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with acquired immunodeficiency syndrome (AIDS)–associated
non-Hodgkin lymphoma often present with multiple poor prognostic features,
including significant tumor burden, advanced immunosuppression, and other
concurrent morbidities. Strategies to manage such complex multiple-disease
cases have often incorporated the assumption that prospects for long-term
survival are poor and that intensive therapy cannot be tolerated and so is
not justified. Since the advent of highly active antiretroviral therapy for
human immunodeficiency virus infection, life expectancy has improved substantially
for patients in whom the virus can be successfully suppressed. Thus, for complicated
cases involving AIDS-associated malignancy, a reassessment of treatment strategies
and the potential for long-term survival is warranted. Here, we present the
case of a patient with poor prognosis due to AIDS-associated lymphoma with
leptomeningeal involvement, advanced immunosuppression, and deep venous thrombosis.
The management of this case illustrates that a multidisciplinary approach
to complex AIDS cases involving malignancy and concurrent morbidity can result
in a return to functional health in affected patients. Successful strategies
for achieving favorable outcomes currently exist with available therapies.
JAMA The Journal of the American Medical Association 05/2001; 285(14):1880-1885. DOI:10.1001/jama.285.14.1880 · 35.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.