<i>BCL2</i> Expression Is a Prognostic Marker for the Activated B-Cell–Like Type of Diffuse Large B-Cell Lymphoma

Iqbal, Javeed; Neppalli, Vishala T.; Wright, George W.; Davé, Bhavana J.; Horsman, Douglas E.; Rosenwald, Andreas; Lynch, James C.; Hans, Christine P.; Weisenburger, Dennis D.; Greiner, Timothy C.; Gascoyne, Randy D.; Campo, Elı́as; Ott, German; Müller-Hermelink, H. K.; Delabie, Jan; Jaffe, Elaine S.; Grogan, Thomas M.; Connors, Joseph M.; Vose, Julie M.; Armitage, Jamés O.; Staudt, Louis M.; Chan, Wing C.

doi:10.1200/jco.2005.03.4264

Cited by 271 publications

(205 citation statements)

References 38 publications

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“…FOXP1 was also predominantly expressed in a similar subset of DLBCL with positive BCL2 [25]. BCL2 protein overexpression has been reported to occur in 24-66 % of cases of DLBCL [26,27]. It has been postulated that in DLBCL changes in FOXP1 and BCL2 were interdependent and that the presence of an additional copy of FOXP1 gene will cause BCL2 protein to be active [28,29].…”

Section: Follow-up and Survivalmentioning

confidence: 99%

“…Several studies have indicated that the expression of FOXP1 in DLBCL is associated with poor clinical outcome [16, 17, Prognostic value of miR-34a and target proteins in gastric lymphomas 439 [23][24][25]. Previous studies with MALT lymphoma indicate that FOXP1 positivity is confined to MALT lymphomas with poor clinical outcome, polymorphic histology, and high risk of transforming into DLBCL [18,26,27]. The previously described role of miR-34a is as a direct link between the tumor suppressor p53 and the oncogenic protein BCL2 [13,14].…”

Section: Follow-up and Survivalmentioning

confidence: 99%

See 1 more Smart Citation

Prognostic significance of miR-34a and its target proteins of FOXP1, p53, and BCL2 in gastric MALT lymphoma and DLBCL

He¹,

Li²,

Zhang³

et al. 2013

Gastric Cancer

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Background Mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL), which are the two most common types of gastric lymphomas, have different clinicopathological features and molecular characteristics with distinct clinical outcomes. Tumor suppressor miR-34a connects the p53 network with forkhead box protein 1 (FOXP1) and BCL2. Here, we investigated the prognostic value of these molecules in gastric MALT lymphoma and DLBCL for use in routine clinical practice. Methods Relative miR-34a expression was detected by quantitative reverse transcriptase-polymerase chain reaction in 20 cases of MALT lymphomas and 20 cases of DLBCLs. Tissue microarray, in situ hybridization, and immunohistochemistry analysis were used to examine the expression of miR-34a and its regulated genes, FOXP1, p53, and BCL2 proteins, in 64 patients with gastric MALT lymphoma and in 58 patients with DLBCL. Helicobacter pylori infection, overall survival (OS), and progression-free survival (PFS) were documented. Results The expression level of miR-34a was markedly decreased in MALT lymphomas and DLBCLs compared to normal gastric tissues and peripheral blood mononuclear cells. miR-34a was present in the cytoplasm and nucleus of lymphocytes. Its expression was significantly downregulated in MALT and DLBCL lymphoma tissues, as compared with normal lymphocytes. The expression level of miR-34a in DLBCL was lower than in MALT lymphoma. FOXP1 was found to be positive in 48 %, p53 in 20 %, and BCL2 in 68 % of MALT lymphoma cases. The corresponding positive rates of these markers in DLBCL were 64, 57, and 52 %, respectively. High expression of FOXP1, p53, and BCL2 was seen in stage III and IV of both types of lymphomas. FOXP1, p53, and BCL2 positivity was associated with poor OS with both lymphoma types but OS with DLBCL was significantly lower than with MALT lymphoma. Conclusions Decreased miR-34a expression and increased FOXP1, p53, and BCL2 coexpression to predict a poor OS for MALT lymphoma and DLBCL patients could become very important prognostic markers in daily clinical work. Further investigation of these changes may be of prognostic significance in clinical practice.

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Section: Follow-up and Survivalmentioning

confidence: 99%

Section: Follow-up and Survivalmentioning

confidence: 99%

Prognostic significance of miR-34a and its target proteins of FOXP1, p53, and BCL2 in gastric MALT lymphoma and DLBCL

He¹,

Li²,

Zhang³

et al. 2013

Gastric Cancer

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“…4A). Strikingly, RP lymphomas were found to exhibit significantly higher IkBa expression levels, further accompanied by substantially higher bcl2 expression levels, thus reminiscent of the NF-kB/Bcl2 network analyzed in Figure 3 and of the genetic hallmark lesions detectable in activated B-cell-like (ABC) DLBCL, the prognostically inferior DLBCL subtype characterized by constitutively active NF-kB signaling due to a variety of activating mutations in the NF-kB pathway and by very high Bcl2 transcript levels (Iqbal et al 2006;Lenz et al 2008b;Compagno et al 2009;Staudt 2010;Nogai et al 2011).…”

Section: Oncogenic Network Determine Opposing Roles Of Nf-kb On Treamentioning

confidence: 99%

Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations

Hua¹,

Kase²,

Dörr³

et al. 2011

Genes Dev.

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In malignancies, enhanced nuclear factor-kB (NF-kB) activity is largely viewed as an oncogenic property that also confers resistance to chemotherapy. Recently, NF-kB has been postulated to participate in a senescence-associated and possibly senescence-reinforcing cytokine response, thereby suggesting a tumor-restraining role for NF-kB. Using a mouse lymphoma model and analyzing transcriptome and clinical data from lymphoma patients, we show here that therapy-induced senescence presents with and depends on active NF-kB signaling, whereas NF-kB simultaneously promotes resistance to apoptosis. Further characterization and genetic engineering of primary mouse lymphomas according to distinct NF-kB-related oncogenic networks reminiscent of diffuse large B-cell lymphoma (DLBCL) subtypes guided us to identify Bcl2-overexpressing germinal center B-cell-like (GCB) DLBCL as a clinically relevant subgroup with significantly superior outcome when NF-kB is hyperactive. Our data illustrate the power of cross-species investigations to functionally test genetic mechanisms in transgenic mouse tumors that recapitulate distinct features of the corresponding human entity, and to ultimately use the mouse model-derived genetic information to redefine novel, clinically relevant patient subcohorts.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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.

show abstract

BCL2 Expression Is a Prognostic Marker for the Activated B-Cell–Like Type of Diffuse Large B-Cell Lymphoma

Abstract: Treating all DLBCL as a single entity ignores the mechanistic differences in BCL2 upregulation and obscures the prognostic significance of BCL2 expression. Hence, the significance of BCL2 and other biomarkers should be assessed in the context of DLBCL subgroups in future studies.

Cited by 271 publications

References 38 publications

Prognostic significance of miR-34a and its target proteins of FOXP1, p53, and BCL2 in gastric MALT lymphoma and DLBCL

Prognostic significance of miR-34a and its target proteins of FOXP1, p53, and BCL2 in gastric MALT lymphoma and DLBCL

Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations

BCL2 mutations in diffuse large B-cell lymphoma

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