Lack of somatic hypermutation of IG VH genes in lymphoid malignancies with t(2;14)(p13;q32) translocation involving the BCL11A gene

Küppers, Ralf; Sawada, Takashi; Satterwhite, Ed; Gesk, Stefan; Harder, Lana; Oscier, David; Tucker, P W; Dyer, Martin J. S.; Siebert, Reiner

doi:10.1038/sj.leu.2402480

Cited by 27 publications

(21 citation statements)

References 19 publications

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“…B-CLL with unmutated IgVH genes has been shown to be associated with an unfavorable prognosis, whereas B-CLL with mutated IgVH genes tend to have a more favorable clinical outcome. The t(2;14)(p13;q32) translocation involving BCL11A in B-CLL has been recently shown to be predominately associated with the unmutated B-CLL group, 23 but no similar studies have been carried out so far in B-CLLs with a t(14;19) translocation. In this study, we have evaluated the IgVH gene status in 26 B-cell lymphomas (14 B-CLL and 12 other B-cell lymphomas) with FISH-proven IG/BCL3 involvement.…”

Section: Discussionmentioning

confidence: 97%

“…The IGH breakpoints in t(14;19)(q32;q13), as in t(2;14) (p13;q32), 23 mostly involve switch regions suggesting that these translocations happened as a defective class switch recombination, which can take place both in T-cell-dependent immune responses in germinal centers or in T-cell-independent immune responses outside such structures. The observation of frequently unmutated IgVH genes and common antigen receptors in B-CLL with IG/BCL3 fusion suggests that this translocation results from an error in class switching during T-cell-independent immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…In three additional cases, different previously described protocols were used. 23,24 Statistical analyses in IG/BCL3-positive cases…”

Section: Igvh Mutation Analysismentioning

confidence: 99%

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A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation

et al. 2007

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The biologic and pathologic features of B-cell malignancies bearing a translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 are still poorly described. Herein we report the results of a comprehensive cytogenetic, fluorescence in situ hybridization (FISH), molecular and histopathological survey of a large series of B-cell malignancies with t(14;19) or variant translocations. A total of 56 B-cell malignancies with a FISHproven BCL3 involvement were identified with the translocation partners being IGH (n ¼ 51), IGL (n ¼ 2), IGK (n ¼ 2) and a non-IG locus (n ¼ 1). Hierarchical clustering of chromosomal changes associated with the t(14;19) indicated the presence of two different groups of IG/BCL3-positive lymphatic neoplasias. The first group included 26 B-cell malignancies of various histologic subtypes containing a relatively high number of chromosomal changes and mostly mutated IgVH genes. This cluster displayed three cytogenetic branches, one with rearrangements in 7q, another with deletions in 17p and a third one with rearrangements in 1q and deletions in 6q and 13q. The second group included 19 cases, mostly diagnosed as B-cell chronic lymphocytic leukemia (B-CLL), and characterized by few additional chromosomal changes (e.g. trisomy 12) and unmutated IgVH genes. In conclusion, our study indicates that BCL3 translocations are not restricted to B-CLL but present in a heterogeneous group of B-cell malignancies.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation

et al. 2007

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“…The whole genomic DNA of isolated cells and controls was preamplified (11). V H , V , and V gene rearrangements were amplified by seminested PCR as described (7,11,12) by using V gene family-specific framework region I primers and J segment-specific primers. These Ig gene PCRs were performed for all samples and controls of cases 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

Epstein–Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction

Kurth

Hansmann

Rajewsky

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

120

101

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To assess the impact of the germinal center (GC) reaction on viral spread in Epstein-Barr virus (EBV) infection, we isolated EBVIn latently infected B cells, distinct EBV gene expression patterns have been described. Besides expression of all latent EBV-encoded transcripts and proteins in latency III (also called growth program), more restricted viral latency gene expression patterns are observed under certain conditions (latencies I and II and latency program during persistence) (1). EBV-encoded genes differentially expressed in these latency programs were shown in vitro to mimic cellular proteins: EBV nuclear antigen (EBNA)-2 expressed in latency III is the main activator of viral and cellular genes and partially employs the Notch signaling pathways; latent membrane protein (LMP)-1 expressed in latencies II and III acts mainly like a constitutively active CD40 receptor; and LMP2A expressed in latencies II and III and perhaps in the latency program during persistence mimics and interferes with B cell antigen receptor signals (2-4).Despite these insights, remarkably little is known about the effects of EBV infection on the cellular differentiation pathways of the infected cells in vivo. Likewise, the primary cellular target(s) of the virus in the B cell compartment is controversial. With respect to the latter, it has been suggested that EBV initially infects naive B cells, which subsequently undergo a germinal center (GC) reaction to gain access to the memory B cell pool, the main reservoir of EBV in healthy virus carriers (5). In the GC reaction, somatic mutations are introduced into V genes of antigen-activated B cells during proliferation. Subsequently, GC B cells are selected for high-affinity binding to the respective antigen and finally differentiate into memory B cells or plasma cells (6). Hence, this model proposed that EBV ϩ B cells behave in the GC like uninfected B cells.However, our recent work on interfollicular EBV ϩ cells in IM tonsils suggested that the pool of infected memory B cells is generated by direct infection and subsequent expansion of these cells (7). Moreover, EBV-infected naive B cells may even be prevented from GC entry, as suggested by the blockade of GC formation in transgenic mice expressing LMP1 in B cells (8). These observations challenge the view that GC passage is a mandatory step in the general strategy of EBV to establish viral persistence.To address these issues directly, we isolated EBV ϩ GC B cells from the tonsils of IM patients and analyzed their rearranged antibody V genes. This analysis allows identification of clonal expansions of B cells, because V gene rearrangements are unique for each newly generated B cell and are inherited by its descendants (6). Moreover, the origin of B cells and their participation in the GC reaction can be examined by the V gene sequence analysis, because somatic mutations are introduced into rearranged V genes in the course of the GC reaction. Thus, naive B cells carry unmutated V gene rearrangements and GC and memory B cells carry mutated...

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“…Interestingly, all cases with t(2;14)(p13;q32) exhibited germline unmutated V H genes. 112 Although this translocation is clearly rare, the BCL11A gene is of interest since like BCL6, it encodes a highly conserved, germinal-center specific, Krü ppel zinc finger transcriptional repressor protein. BCL6 and BCL11A interact directly indicating that they may function to control the same subset of genes in mature B cells.…”

Section: Bcl11a (2p13) Translocationsmentioning

confidence: 99%

The configuration of the immunoglobulin genes in B cell chronic lymphocytic leukemia

Dyer

Oscier

2002

Leukemia

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Lack of somatic hypermutation of IG VH genes in lymphoid malignancies with t(2;14)(p13;q32) translocation involving the BCL11A gene

Cited by 27 publications

References 19 publications

A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation

A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation

Epstein–Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction

The configuration of the immunoglobulin genes in B cell chronic lymphocytic leukemia

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