BCL2 mutations in diffuse large B-cell lymphoma

Abstract

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.

Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma

“…Mutations in the BCL2 gene are common in certain subtypes of B-cell lymphoma such as diffuse large cell lymphoma (DLBCL) and follicular lymphoma, but these are rarely detected in MCL, CLL, and primary mediastinal B-cell lymphoma. 38,39 Interestingly, most of the 77 nonsynonymous BCL2 mutations found in 2 series comprising 353 patients with DLBCL occurred in the flexible loop domain containing the P53-binding site, but only one affected the BH3 domain. 38,39 The fact that only 1 of 353 patients with untreated lymphomas (0.0028%) showed mutations in this BCL2 domain strongly suggests that the F101C and F101L mutations found in the murine lymphoma cells are related to the continuous ABT-199 exposure.…”

“…38,39 Interestingly, most of the 77 nonsynonymous BCL2 mutations found in 2 series comprising 353 patients with DLBCL occurred in the flexible loop domain containing the P53-binding site, but only one affected the BH3 domain. 38,39 The fact that only 1 of 353 patients with untreated lymphomas (0.0028%) showed mutations in this BCL2 domain strongly suggests that the F101C and F101L mutations found in the murine lymphoma cells are related to the continuous ABT-199 exposure. To functionally characterize such Bcl2 mutations, competitive binding experiments were performed using a fluorescent BH3-Bad peptide.…”

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

“…60 They consistently spare the BH3 domain, which is necessary for its antiapoptotic function and is the binding site for BH3 mimetics such as venetoclax.…”

A rare CD5-positive subgroup of diffuse large B-cell lymphoma – clinical, morphological and immunophenotypic features in Polish patients

“…This observation is a notion towards the association between FOXP1 expression and clinical course of the lymphoma. However, Nyman et al suggest that the prognostic significance of FOXP1 is doubtful, especially in contrast to BCL2 [13], whose unfavorable impact in DLBCL remains firmly documented [13,14,15], and may be further enhanced in cases with co-expression of CD10 [16]. High BCL2 expression, found in 40-60% of the DLBCL population, leads to uncontrolled proliferation of lymphoid cells [14].…”

“…Favorable prognostic factors include, among others, the expression of CD30 [7], BCL6 [8] and a low proliferative index [9]. Adverse prognostic factors comprise the expression of cyclin D2 [10], CD138 [8], CD44 [11], p53 [12], BCL2 [13,14,15], and more importantly, the co-expression of BCL2 and CD10 [16]. The role of cyclin D3 [17,18], FOXP1 [13,19] and CD10 as prognostic factors in patients with DLBCL is not fully elucidated on the basis of the available literature [20,21,22].…”