BCL2 Predicts Survival in Germinal Center B-cell–like Diffuse Large B-cell Lymphoma Treated with CHOP-like Therapy and Rituximab

Iqbal, Javeed; Meyer, Paul N.; Smith, Lynette M.; Johnson, Nathalie A.; Vose, Julie M.; Greiner, Timothy C.; Connors, Joseph M.; Staudt, Louis M.; Rimsza, Lisa M.; Jaffe, Elaine S.; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elı́as; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Gascoyne, Randy D.; Armitage, Jamés O.; Weisenburger, Dennis D.; Chan, Wing C.

doi:10.1158/1078-0432.ccr-11-0267

Cited by 146 publications

(127 citation statements)

References 52 publications

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“…When cases were stratified into GCB-and ABC-DLBCL, we showed that p52 expression in GCB-DLBCL conferred better outcome. As CD30 and BCL2 are known independent prognostic factors in DLBCL, 27,39 we controlled for each of those biomarkers and evaluated the effect of p52 expression on OS in GCB-DLBCL. When BCL2 was controlled, the beneficial effect of p52 expression remained in patients with DLBCL without BCL2 expression (P = 0.0477), but only a trend toward a beneficial effect was observed in patients with DLBCL with BCL2 expression (P = 0.2275).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

Xu-Monette

et al. 2015

Modern Pathology

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Nuclear factor-κB (NF-κB) is a transcription factor with a well-described oncogenic role. Study for each of five NF-κB pathway subunits was only reported on small cohorts in diffuse large B-cell lymphoma (DLBCL). In this large cohort (n = 533) of patients with de novo DLBCL, we evaluated the protein expression frequency, gene expression signature, and clinical implication for each of these five NF-κB subunits. Expression of p50, p52, p65, RELB, and c-Rel was 34%, 12%, 20%, 14%, and 23%, whereas p50/p65, p50/c-Rel, and p52/RELB expression was 11%, 11%, and 3%, respectively. NF-κB subunits were expressed in both germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, but p50 and p50/c-Rel were associated with ABC-DLBCL. p52, RELB, and p52/ RELB expressions were associated with CD30 expression. p52 expression was negatively associated with BCL2 (B-cell lymphoma 2) expression and BCL2 rearrangement. Although p52 expression was associated with better progression-free survival (PFS) (P = 0.0170), singular expression of the remaining NF-κB subunits alone did not show significant prognostic impact in the overall DLBCL cohort. Expression of p52/RELB was associated with better overall survival (OS) and PFS (P = 0.0307 and P = 0.0247). When cases were stratified into GCB-and

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Section: Discussionmentioning

confidence: 99%

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

Xu-Monette

et al. 2015

Modern Pathology

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“…11 The addition of rituximab to chemotherapy may overcome the impact of BCL2 expression on prognosis; 12 however, BCL2 expression remains relevant when analysis is restricted to specific molecular subtypes of DLBCL. 7,13,14 Indeed, drugs that target BCL2 are being investigated in clinical trials, thus BCL2 mutations may be clinically important in the future.…”

Section: Introductionmentioning

confidence: 99%

BCL2 mutations in diffuse large B-cell lymphoma

et al. 2011

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BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-kB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.Leukemia ( BCL2, discovered because of its involvement in t(14;18) in follicular lymphoma (FL), 3 has a central role in the inhibition of apoptosis. 4 BCL2 is normally transiently expressed during B-cell maturation. The t(14;18) translocation causes constitutive overexpression of BCL2 by juxtaposing it to immunoglobulin heavy chain gene enhancer elements. This translocation is found in B20% of DLBCL, 5 most often in the GCB subtype of DLBCL. 6 Other mechanisms of BCL2 deregulation, more often observed in ABC DLBCLs, include amplification of the BCL2 gene or its transcriptional upregulation through constitutive activation of the nuclear factor-kB pathway. 7 Saito et al. 8 reported that the BCL2 promoter can also be aberrantly hypermutated in DLBCL, which may prevent its inhibition by MIZ1 and BCL6. 8 They found a high number of mutations in BCL2 and suggested that the mutations described were the result of somatic hypermutation (SHM). Mutations in BCL2 have been shown to cause false-negative protein expression results in immunohistochemistry assays in FL; 9,10 however, no large study has so far investigated whether this occurs in DLBCL.

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“…Introduction of rituximab (MoAb anti CD20) into the treatment protocol is beneficial for patients in both the GCB and ABC prognostic subgroups. However, the treatment outcome in GCB patients with t(14;18) is not as good as in those from the ABC subgroup 12 . The second most frequent cytogenetic aberration in the GCB subgroup is translocation leading to rearrangement of the MYC gene (8q24), reported in as many as 22% of patients 13 .…”

Section: Gcb D Lbclmentioning

confidence: 91%

“…Expression of BCL2 is associated with poor prognosis in patients in the ABC subtype but not in GCB DLBCL (ref. 12 ). The ABC molecular subgroup of DLBCL is derived from B cells which differentiate and proceed to the plasma cell stage.…”

Section: Abc Dlbclmentioning

confidence: 99%

See 1 more Smart Citation

Cytogenetics and molecular cytogenetics in diffuse large B-cell lymphoma (DLBCL)

Nedomova¹,

Papajík²,

Procházka³

et al. 2013

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Diffuse large B-cell lymphoma (DLBCL) accounts for up to 40% of all non-Hodgkin's lymphomas diagnosed in the western hemisphere. Determination of the gene expression profile has confirmed the physiological heterogeneity of the disease and defined three molecular prognostic subgroups -germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal B-cell lymphoma (PMBL) -with different gene expression and prognosis. Methods and Results. This review covers current knowledge on the most frequent recurrent cytogenetic and molecular cytogenetic aberrations in molecular DLBCL subgroups. Conclusions. Cytogenetic and molecular cytogenetic techniques used to determine nonrandom chromosomal aberrations in patients with DLBCL have revealed the incidence of frequent cytogenetic aberrations in the subgroups reported, suggesting their potential use for more accurate prognostic stratification of DLBCL, contributing to personalized selection of the most effective therapy.

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BCL2 Predicts Survival in Germinal Center B-cell–like Diffuse Large B-cell Lymphoma Treated with CHOP-like Therapy and Rituximab

Cited by 146 publications

References 52 publications

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

BCL2 mutations in diffuse large B-cell lymphoma

Cytogenetics and molecular cytogenetics in diffuse large B-cell lymphoma (DLBCL)

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