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Kieron Dunleavy,
Stefania Pittaluga,
Lauren S Maeda,
Ranjana Advani,
Clara C Chen,
Julie Hessler,
Seth M Steinberg,
Cliona Grant,
George Wright,
Gaurav Varma, Louis M Staudt,
Elaine S Jaffe,
Wyndham H Wilson
[show abstract]
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ABSTRACT: Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.
We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.
The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.
Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).
New England Journal of Medicine 04/2013; 368(15):1408-16. · 53.30 Impact Factor
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Laurence Lamy,
Vu N Ngo,
N C Tolga Emre,
Arthur L Shaffer,
Yandan Yang,
Erming Tian,
Vinod Nair,
Michael J Kruhlak,
Adriana Zingone,
Ola Landgren, Louis M Staudt
[show abstract]
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ABSTRACT: We performed a loss-of-function RNA interference screen to define therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma.
Cancer cell 03/2013; · 25.29 Impact Factor
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Michael Chiorazzi,
Lixin Rui,
Yandan Yang,
Michele Ceribelli,
Nima Tishbi,
Carine W Maurer,
Stella M Ranuncolo,
Hong Zhao,
Weihong Xu,
Wing-Chung C Chan,
Elaine S Jaffe,
Randy D Gascoyne,
Elias Campo,
Andreas Rosenwald,
German Ott,
Jan Delabie,
Lisa M Rimsza,
Shai Shaham, Louis M Staudt
[show abstract]
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ABSTRACT: Cell death is a common metazoan cell fate, and its inactivation is central to human malignancy. In Caenorhabditis elegans, apoptotic cell death occurs via the activation of the caspase CED-3 following binding of the EGL-1/BH3-only protein to the antiapoptotic CED-9/BCL2 protein. Here we report a major alternative mechanism for caspase activation in vivo involving the F-box protein DRE-1. DRE-1 functions in parallel to EGL-1, requires CED-9 for activity, and binds to CED-9, suggesting that DRE-1 promotes apoptosis by inactivating CED-9. FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death. Moreover, some human diffuse large B-cell lymphomas have inactivating mutations in FBXO10 or express FBXO10 at low levels. Our results suggest that DRE-1/FBXO10 is a conserved regulator of apoptosis.
Proceedings of the National Academy of Sciences 03/2013; 110(10):3943-8. · 9.68 Impact Factor
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ABSTRACT: Signalling through the B cell receptor (BCR) is central to the development and maintenance of B cells. In light of the numerous proliferative and survival pathways activated downstream of the BCR, it comes as no surprise that malignant B cells would co-opt this receptor to promote their own growth and survival. However, direct evidence for BCR signalling in human lymphoma has only come to light recently. Roles for antigen-dependent and antigen-independent, or tonic, BCR signalling have now been described for several different lymphoma subtypes. Furthermore, correlative data implicate antigen-dependent BCR signalling in many other forms of lymphoma. A host of therapeutic agents targeting effectors of the BCR signalling pathway are now in clinical trials and have shown initial success against multiple forms of lymphoma.
dressNature Reviews Drug Discovery 03/2013; 12(3):229-43. · 29.01 Impact Factor
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Cold Spring Harbor perspectives in biology 01/2013; 5(1). · 9.40 Impact Factor
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[show abstract]
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ABSTRACT: High-throughput mRNA sequencing (RNA-seq) uses massively parallel sequencing to allow an unbiased analysis of both genome-wide transcription levels and mutation status of a tumor. In the RNA-seq method, complementary DNA (cDNA) is used to generate short sequence reads by immobilizing millions of amplified DNA fragments onto a solid surface and performing the sequence reaction. The resulting sequences are aligned to a reference genome or transcript database to create a comprehensive description of the analyzed transcriptome. This chapter describes a protocol to perform RNA-seq using the Illumina sequencing platform, presents sequencing data quality metrics and outlines a bioinformatic pipeline for sequence alignment, digital gene expression, and mutation discovery.
Methods in molecular biology (Clifton, N.J.) 01/2013; 971:295-312.
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ABSTRACT: The activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL) is an aggressive lymphoma that is addicted to NF-κB signaling through the CARD11-BCL10-MALT1 complex. In this issue of Cancer Cell, Nagel and colleagues and Fontan and colleagues describe MALT1 inhibitors suitable for clinical use that are selectively toxic to this malignancy.
Cancer cell 12/2012; 22(6):706-7. · 25.29 Impact Factor
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Alyssa Bouska,
Timothy McKeithan,
Karen E Deffenbacher,
Cynthia Lachel,
George W. Wright,
Javeed Iqbal,
Lynette M. Smith,
Zhongfeng Liu,
Can Kucuk,
Francesco Bertoni, [......],
Dennis D Weisenburger,
Timothy C. Greiner,
Randy D. Gascoyne,
Andreas Rosenwald,
Elias Campo,
Lisa M. Rimsza,
Jan Delabie,
Elaine S. Jaffe, Louis M. Staudt,
MD1 Wing-Chung Chan
American Society of Hematology; 12/2012
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Andrew L Snow,
Wenming Xiao,
Jeffrey R Stinson,
Wei Lu,
Benjamin Chaigne-Delalande,
Lixin Zheng,
Stefania Pittaluga,
Helen F Matthews,
Roland Schmitz,
Sameer Jhavar, [......],
Lela Kardava,
Wei Wang,
Ian T Lamborn,
Huie Jing,
Mark Raffeld,
Susan Moir,
Thomas A Fleisher, Louis M Staudt,
Helen C Su,
Michael J Lenardo
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ABSTRACT: Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions, but constitutive NF-κB activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)-induced NF-κB activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-κB activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.
Journal of Experimental Medicine 11/2012; · 13.85 Impact Factor
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Nature Immunology 11/2012; 13(11):1029-31. · 26.01 Impact Factor
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Cancer Research 09/2012; · 7.86 Impact Factor
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Roland Schmitz,
Ryan M Young,
Michele Ceribelli,
Sameer Jhavar,
Wenming Xiao,
Meili Zhang,
George Wright,
Arthur L Shaffer,
Daniel J Hodson,
Eric Buras, [......],
James R Cook,
Dennis D Weisenburger,
Wing C Chan,
Stefania Pittaluga,
Wyndham Wilson,
Thomas A Waldmann,
Martin Rowe,
Sam M Mbulaiteye,
Alan B Rickinson, Louis M Staudt
[show abstract]
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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.
Nature 08/2012; 490(7418):116-20. · 36.28 Impact Factor
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Nathalie A Johnson,
Graham W Slack,
Kerry J Savage,
Joseph M Connors,
Susana Ben-Neriah,
Sanja Rogic,
David W Scott,
King L Tan,
Christian Steidl,
Laurie H Sehn, [......],
Raymond R Tubbs,
Dennis D Weisenburger,
Elias Campo,
Andreas Rosenwald,
German Ott,
Jan Delabie,
Christina Holcroft,
Elaine S Jaffe, Louis M Staudt,
Randy D Gascoyne
[show abstract]
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ABSTRACT: PURPOSE Diffuse large B-cell lymphoma (DLBCL) is curable in 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MYC translocations, with or without BCL2 translocations, have been associated with inferior survival in DLBCL. We investigated whether expression of MYC protein, with or without BCL2 protein expression, could risk-stratify patients at diagnosis. PATIENTS AND METHODS We determined the correlation between presence of MYC and BCL2 proteins by immunohistochemistry (IHC) with survival in two independent cohorts of patients with DLBCL treated with R-CHOP. We further determined if MYC protein expression correlated with high MYC mRNA and/or presence of MYC translocation. Results In the training cohort (n = 167), MYC and BCL2 proteins were detected in 29% and 44% of patients, respectively. Concurrent expression (MYC positive/BCL2 positive) was present in 21% of patients. MYC protein correlated with presence of high MYC mRNA and MYC translocation (both P < .001), but the latter was less frequent (both 11%). MYC protein expression was only associated with inferior overall and progression-free survival when BCL2 protein was coexpressed (P < .001). Importantly, the poor prognostic effect of MYC positive/BCL2 positive was validated in an independent cohort of 140 patients with DLBCL and remained significant (P < .05) after adjusting for presence of high-risk features in a multivariable model that included elevated international prognostic index score, activated B-cell molecular subtype, and presence of concurrent MYC and BCL2 translocations. CONCLUSION Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.
Journal of Clinical Oncology 07/2012; 30(28):3452-9. · 18.37 Impact Factor
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Anamarija M Perry,
Teresa M Cardesa-Salzmann,
Paul N Meyer,
Luis Colomo,
Lynette M Smith,
Kai Fu,
Timothy C Greiner,
Jan Delabie,
Randy D Gascoyne,
Lisa Rimsza, [......],
Raymond Tubbs,
James R Cook, Louis M Staudt,
Joseph M Connors,
Laurie H Sehn,
Julie M Vose,
Armando López-Guillermo,
Elias Campo,
Wing C Chan,
Dennis D Weisenburger
[show abstract]
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ABSTRACT: Biologic factors that predict the survival of patients with a diffuse large B-cell lymphoma, such as cell of origin and stromal signatures, have been discovered by gene expression profiling. We attempted to simulate these gene expression profiling findings and create a new biologic prognostic model based on immunohistochemistry. We studied 199 patients (125 in the training set, 74 in the validation set) with de novo diffuse large B-cell lymphoma treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies, and immunohistochemical stains were performed on paraffin-embedded tissue microarrays. In the model, 1 point was awarded for each adverse prognostic factor: nongerminal center B cell-like subtype, SPARC (secreted protein, acidic, and rich in cysteine) < 5%, and microvascular density quartile 4. The model using these 3 biologic markers was highly predictive of overall survival and event-free survival in multivariate analysis after adjusting for the International Prognostic Index in both the training and validation sets. This new model delineates 2 groups of patients, 1 with a low biologic score (0-1) and good survival and the other with a high score (2-3) and poor survival. This new biologic prognostic model could be used with the International Prognostic Index to stratify patients for novel or risk-adapted therapies.
Blood 06/2012; 120(11):2290-6. · 9.90 Impact Factor
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Yibin Yang,
Arthur L Shaffer,
N C Tolga Emre,
Michele Ceribelli,
Meili Zhang,
George Wright,
Wenming Xiao,
John Powell,
John Platig,
Holger Kohlhammer, [......],
Weihong Xu,
Joseph J Buggy,
Sriram Balasubramanian,
Lesley A Mathews,
Paul Shinn,
Rajarshi Guha,
Marc Ferrer,
Craig Thomas,
Thomas A Waldmann, Louis M Staudt
[show abstract]
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ABSTRACT: Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.
Cancer cell 06/2012; 21(6):723-37. · 25.29 Impact Factor
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Javeed Iqbal,
Yulei Shen,
Yanyan Liu,
Kai Fu,
Elaine S Jaffe,
Cuiling Liu,
Zhongfeng Liu,
Cynthia M Lachel,
Karen Deffenbacher,
Timothy C Greiner, [......],
Jan Delabie,
Elias Campo,
Rita M Braziel,
James R Cook,
Raymond R Tubbs,
Randy D Gascoyne,
James O Armitage,
Dennis D Weisenburger,
Timothy W McKeithan,
Wing C Chan
[show abstract]
[hide abstract]
ABSTRACT: miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1-positive MCL (n = 30) and cyclin D1-negative MCL (n = 7) and compared them with small lymphocytic leukemia/lymphoma (n = 12), aggressive B-cell lymphomas (n = 138), normal B-cell subsets, and stromal cells. We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNA classifier showed consistent results in formalin-fixed paraffin-embedded tissues and was able to distinguish cyclin D1-negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators.
Blood 04/2012; 119(21):4939-48. · 9.90 Impact Factor
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ABSTRACT: Derangement of the nuclear factor κB (NF-κB) pathway initiates and/or sustains many types of human cancer. B-cell malignancies are particularly affected by oncogenic mutations, translocations, and copy number alterations affecting key components the NF-κB pathway, most likely owing to the pervasive role of this pathway in normal B cells. These genetic aberrations cause tumors to be 'addicted' to NF-κB, which can be exploited therapeutically. Since each subtype of lymphoid cancer utilizes different mechanisms to activate NF-κB, several different therapeutic strategies are needed to address this pathogenetic heterogeneity. Fortunately, a number of drugs that block signaling cascades leading to NF-κB are in early phase clinical trials, several of which are already showing activity in lymphoid malignancies.
Immunological Reviews 03/2012; 246(1):359-78. · 11.15 Impact Factor
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Karen E Deffenbacher,
Javeed Iqbal,
Warren Sanger,
Yulei Shen,
Cynthia Lachel,
Zhongfeng Liu,
Yanyan Liu,
Megan S Lim,
Sherrie L Perkins,
Kai Fu, [......],
Andreas Rosenwald,
German K Ott,
Jan Delabie,
Elias Campo,
Randy D Gascoyne,
Mitchell S Cairo,
Dennis D Weisenburger,
Timothy C Greiner,
Thomas G Gross,
Wing C Chan
[show abstract]
[hide abstract]
ABSTRACT: Burkitt lymphoma (BL) predominates in pediatric patients, whereas diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared with adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between corresponding pediatric and adult tumors. Predominance (6:1) of the germinal center B-cell subtype to activated B-cell subtype was found among pediatric DLBCL. Two cases were molecularly classified as primary mediastinal B-cell lymphoma. We observed frequent abnormalities in 8q24 in pediatric DLBCL, including MYC rearrangement in 31% (5 of 16) and gain or amplification in 50% (6 of 12) nonrearranged cases. MYC rearrangement was present in 96% (23 of 24) BL cases. Array-based CGH analysis identified abnormalities that are shared between adult and pediatric DLBCL (+12q15, +19q13, -6q), and abnormalities unique to the pediatric cases (-4p14, -19q13.32, +16p11.2), suggesting distinct pathogenetic mechanisms relative to age. Elucidation of the underlying target genes may provide insight into factors that modulate outcome and could provide potential novel therapeutic targets with less toxicity for pediatric patients with B-cell non-Hodgkin lymphoma.
Blood 02/2012; 119(16):3757-66. · 9.90 Impact Factor
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Ellen Leich,
Alberto Zamo,
Heike Horn,
Eugenia Haralambieva,
Bernhard Puppe,
Randy D Gascoyne,
Wing-Chung Chan,
Rita M Braziel,
Lisa M Rimsza,
Dennis D Weisenburger,
Jan Delabie,
Elaine S Jaffe,
Jude Fitzgibbon, Louis M Staudt,
Hans-Konrad Mueller-Hermelink,
Mariarita Calaminici,
Elias Campo,
German Ott,
Luis Hernández,
Andreas Rosenwald
[show abstract]
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ABSTRACT: A total of 90% of follicular lymphomas (FLs) harbor the translocation t(14;18) leading to deregulated BCL2 expression. Conversely, 10% of FLs lack the t(14;18), and the majority of these FLs do not express BCL2. The molecular features of t(14;18)-negative FLs remain largely unknown. We performed microRNA expression analysis in 32 FL grades 1 to 3A, including 17 t(14;18)-positive FLs, 9 t(14;18)-negative FLs without BCL2 expression, and 6 t(14;18)-negative FLs with BCL2 expression. MicroRNA profiles were correlated with corresponding mRNA expression patterns, and potential targets were investigated by quantitative PCR and immunohistochemistry in an independent validation series of 83 FLs. Statistical analysis identified 17 microRNAs that were differentially expressed between t(14;18)-positive FLs and t(14;18)-negative FLs. The down-regulation of miR-16, miR-26a, miR-101, miR-29c, and miR138 in the t(14;18)-negative FL subset was associated with profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis, and B-cell differentiation. miR-16 target CHEK1 showed increased expression in t(14;18)-negative FLs, whereas TCL1A expression was reduced, in line with a partial loss of the germinal center B-cell phenotype in this FL subset. In conclusion, t(14;18)-negative FL have distinct microRNA profiles that are associated with an increased proliferative capacity and a "late" germinal center B-cell phenotype.
Blood 09/2011; 118(20):5550-8. · 9.90 Impact Factor
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Javeed Iqbal,
Paul N Meyer,
Lynette M Smith,
Nathalie A Johnson,
Julie M Vose,
Timothy C Greiner,
Joseph M Connors, Louis M Staudt,
Lisa Rimsza,
Elaine Jaffe, [......],
German Ott,
Jan Delabie,
Elias Campo,
Rita M Braziel,
James R Cook,
Raymond R Tubbs,
Randy D Gascoyne,
James O Armitage,
Dennis D Weisenburger,
Wing C Chan
[show abstract]
[hide abstract]
ABSTRACT: We have previously shown the prognostic significance of BCL2 expression in the activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) patients treated with cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) or CHOP-like therapy. However, after the inclusion of rituximab (R) in the CHOP regimen, several conflicting observations about the prognostic value of BCL2 expression have been reported.
We evaluated the R-CHOP cohort of 221 DLBCL cases with gene expression profiling data. BCL2 protein (n = 169), mRNA (n = 221) expression, and t(14;18) (n = 144) were correlated with clinical outcome. The CHOP cohort (n = 181) was used for comparative analysis.
BCL2 protein expression has significant impact on overall survival (OS) and event-free survival (EFS) in DLBCL (OS, P = 0.009; EFS, P = 0.001) and GCB-DLBCL (OS, P = 0.03; EFS, P = 0.002) but not in ABC-DLBCL in the R-CHOP cohort. The survival differences for EFS in GCB-DLBCL were still observed in multivariate analysis. At the mRNA level, this correlation was observed in EFS in DLBCL (P = 0.006), but only a trend was observed in GCB-DLBCL (P = 0.09). The t(14;18) was detected in 34% of GCB-DLBCL but was not associated with significant differences in survival. Gene enrichment analysis identified significant enrichment of the DLBCL "stromal-1" signatures and hypoxia-inducible factor 1 (HIF1-α) signature in BCL2(-)GCB-DLBCL, whereas T(FH) cell signatures were enriched in BCL2(+)GCB-DLBCL.
The prognostic significance of BCL2 has changed after inclusion of rituximab in the treatment protocol and is observed in the GCB-DLBCL rather than the ABC-DLBCL. Although rituximab has benefited patients in both DLBCL subgroups, the BCL2(+)GCB-DLBCL seems to receive less benefit from this treatment and may require other novel therapeutic intervention.
Clinical Cancer Research 09/2011; 17(24):7785-95. · 7.74 Impact Factor
