Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies

Abstract

Chromosomal translocation t(6;14)(p21.1; q32.3) has been reported as a rare but recurrent event not only in myeloma and plasma cell leukemia but also in diffuse large B-cell non-Hodgkin lymphoma (B-NHL) (diffuse large B-cell lymphoma [DLBCL]) and splenic lymphoma with villous lymphocytes (SLVL); however, the nature of the target gene(s) has not been determined. This study identified t(6; 14)(p21.1;q32.3) in 3 cases of transformed extranodal marginal zone B-NHL, in 1 case of SLVL, and in 1 case of a low-grade B-cell lymphoproliferative disorder. In a sixth case, a CD5 ؉ DLBCL, the translocation was identified by molecular cloning in the absence of cytogenetically detectable change. Two chromosomal translocation breakpoints were cloned by using long-distance inverse polymerase chain reaction methods. IntroductionThe lymphomas and leukemias of mature B cells are a biologically and histologically heterogeneous group of malignancies. 1 Their molecular pathogenesis for the most part remains unknown, although cloning of chromosomal translocations targeted to the immunoglobulin (IG) loci continues to allow the identification of novel dominant oncogenes and to define new pathogenic mechanisms. 2 These translocations result in the deregulated expression of genes involved in several pathways, including the control of programmed cell death (apoptosis) and proliferation.IG translocations that involve genes controlling progression through the cell cycle have been described. Cyclin D1 (CCND1) on chromosome 11q13 is involved in the t(11;14)(q13;q32.3). This translocation is found in nearly all cases of mantle cell lymphoma but also in some cases of myeloma, in marginal zone malignancies, such as splenic lymphoma with villous lymphocytes (SLVL), and in B-cell prolymphocytic leukemia. [3][4][5][6] The cyclin-dependent kinase gene (CDK6) in chromosome band 7q22 is involved in t(7;14)(q22;q32) or more commonly in t(2;7)(p12;q22); these translocations appear to be specific for a subset of SLVL. 7,8 The involvement of the cell-cycle regulatory genes in marginal zone B-cell malignancies was unanticipated, because they are characteristically indolent diseases. Whether these genes might have functions in B-cell differentiation other than cell-cycle regulation in mature B cells is not yet clear; cyclin D3 expression, for example, is associated with differentiation of some cell types. 9 Cytogenetic abnormalities of chromosome band 6p21 reported in mature B-cell malignancies are various and include translocations, amplifications, and deletions. 10,11 Such translocations in diffuse large B-cell lymphoma (DLBCL) often involve the BCL6 gene on chromosome band 3q27 and may juxtapose BCL6 with either the histone H4 gene or the PIM1 oncogene. 12,13 The t(6;14)(p12ϳp21;q32) has been previously reported in a variety of B-cell malignancies, principally in myeloma and plasma cell leukemia but also in DLBCL and splenic marginal zone lymphomas (SMZLs). 14-18 Here we report the recurrent involvement of a For personal use only. on May 12, 2018. by gues...

Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index

“…8 None of the cases we analyzed by FISH showed the t(6;14) translocation, suggesting that this may be an extremely uncommon event in FL. Nevertheless, we found extrasignals of the cyclin D3 gene in 2 of 34 cases.…”

“…33 It has been suggested that, similarly to cyclin D1 in mantle cell lymphoma and plasma cell myeloma, cyclin D3 may be deregulated in hematopoietic disorders as a consequence of the t(6;14) translocation. 7,8 In particular, Shaughnessy et al 7 and Sonoki et al 8 found that cyclin D3 expression was associated with the t(6;14) translocation in approximately 5% of plasma cell myelomas and in sporadic cases of NHLs, respectively. In the above study, however, cyclin D3 IR has not been assayed in a matched series of cases lacking the t(6;14) translocation.…”

“…The cyclin D3 locus was investigated using the PAC clone RP5-973N23 (red signal). 8 The probes were preliminarily tested on a KMM-1 plasma cell myeloma (PCM) cell line carrying the t(6;14) translocation that juxtaposes the cyclin D3 gene with 3Ј IgH enhancer sequences. For the evaluation of the results, we first assessed the background of false positive interphase nuclei showing coincidentally colocalized signals by analyzing 200 nuclei extracted from the 10 hyperplastic lymph nodes.…”

“…5,6 Cyclin D3 maps to the 6p21 locus and may be deregulated in approximately 5% of plasma cell myelomas and in sporadic cases of non-Hodgkin's lymphomas (NHLs) as a consequence of the t(6;14)(p21.1;q32.3) translocation, which juxtaposes the cyclin D3 gene to the 3Ј IgH sequences. 7,8 Interestingly, it has been recently demonstrated that cyclin D3 overexpression is effective in predisposing mouse fibroblast cell lines to malignant transformation. 9 Moreover, amplification of the cyclin D3 gene and/or the 6p21 locus has been documented in up to 30% of NHLs.…”

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

“…Translocations that fuse CCND3 to IgH or other genes are observed in human B lineage lymphomas including Mantle Cell Lymphoma, Multiple Myeloma, and Diffuse Large B Cell Lymphoma. [30][31][32] These translocations have been proposed to drive cancer by accelerating proliferation through transcriptional upregulation of CYCLIN D3 protein. Considering that B lineage cancers with CCND3 translocations harbor additional genomic lesions arising from aberrant repair of DSBs, our data suggest that formation of CCND3 translocations in immature B cells may lead to mature B cell malignancies by disrupting regulation of G1-to-S progression in developing B cells.…”