Clustering of extensive somatic mutations in the variable region of an immunoglobulin heavy chain gene from a human B cell lymphoma

Cleary, Michael L.; Meeker, Timothy C.; Levy, Shoshana; Lee, Elizabeth; Trela, Martha; Sklar, Jeffrey; Levy, Ronald

doi:10.1016/0092-8674(86)90488-5

Cited by 255 publications

(125 citation statements)

References 30 publications

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“…This is the most-common chromosomal translocation in human cancer, accounting for almost all follicular lymphomas. (3,(6)(7)(8)(9)(10)(11) The t(14,18)(q32;q21) translocation occurs at the bcl-2 gene of chromosome 18, activates the protooncogene bcl-2, leads to bcl-2 overexpression and aborts programmed cell death, which in turn leads to the lymphoma. (3,5,12) Although the bcl-2 gene is more than 200 kb long, T-cells or B-cells about 75% of translocations occur within a relatively small 150 bp sequence located in the untranslated portion of the third exon, designated as the major breakpoint region (Mbr) ( Fig.…”

Section: Lymphoid Translocations: An Overviewmentioning

confidence: 99%

DNA structures at chromosomal translocation sites

Raghavan

Lieber

2006

BioEssays

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SummaryIt has been unclear why certain defined DNA regions are consistently sites of chromosomal translocations. Some of these are simply sequences of recognition by endogenous recombination enzymes, but most are not. Recent progress indicates that some of the most common fragile sites in human neoplasm assume non-B DNA structures, namely deviations from the Watson-Crick helix. Because of the single strandedness within these non-B structures, they are vulnerable to structure-specific nucleases. Here we summarize these findings and integrate them with other recent data for non-B structures at sites of consistent constitutional chromosomal translocations.

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Section: Lymphoid Translocations: An Overviewmentioning

confidence: 99%

DNA structures at chromosomal translocation sites

Raghavan

Lieber

2006

BioEssays

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“…Follicular NHL cells are frozen in the centroblastic/centrocytic differentiation stage in which the somatic mutation machinery remains active. [61][62][63][64] The somatic mutation profiles of follicular NHL cells provide evidence that these neoplastic cells remain under continuous affinity selection, 65,66 so antigen-driven proliferation processes are most likely involved in the maintenance of the malignant cell population. 20 Bcl-2 transgenic mice are excellent tools to demonstrate the tumorigenicity of deregulated bcl-2 gene expression.…”

Section: T(14;18) Deregulates Bcl-2 Gene Expressionmentioning

confidence: 99%

t(14;18), a journey to eternity

Meijerink

1997

Leukemia

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The t(14;18) is the most frequent chromosomal aberration observed in follicular non-Hodgkin's lymphoma (NHL), and less frequently in diffuse large cell lymphoma (DLCL). The t(14;18) does not affect overall survival in follicular NHL or DLCL. It provides a unique lymphoma-specific marker that can be used to quantify residual disease during treatment, and may forward evaluation of new treatment protocols. The t(14;18) results in the deregulation of bcl-2, a proto-oncogene that protects against induction of programmed cell death (PCD). Nowadays, a whole family of bcl-2-related genes has been identified and consist of members which can either protect or promote induction of PCD. The family members form protein dimers, and the relative abundance of specific dimers regulates the cellular sensitivity to death signals (the rheostat model). Aberrant expression of different family members in several types of malignancies alter the cellular rheostat and thereby promote cellular resistance to chemotherapy.

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“…Thus, they concluded that in some cases biclonal lymphomas could develop. However, FL represents a stage of B cell development at which somatic mutation of the Ig genes is occurring at a high rate (36,41) . Mutations can occur in restriction enzyme sites and alter the size of bands in a Southern analysis (11); therefore, the absence of concordant bands does not necessarily indicate multiclonal origins .…”

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confidence: 99%

Histologic transformation of follicular lymphoma to diffuse lymphoma represents tumor progression by a single malignant B cell.

Zelenetz

Chen

Levy

1991

The Journal of Experimental Medicine

105

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SummaryTo investigate the clonal relationship between follicular lymphoma (FL) and transformed diffuse lymphoma (tDL), we examined the expression of tumor idiotype, immunoglobulin (Ig) gene rearrangements and sequence of Ig variable genes in paired tissue specimens. All 16 cases analyzed expressed surface immunoglobulin (slg) on both the FL and the OL, though the immunophenotype of one case of FL could not be definitively determined . In 14 of 15 cases, the surface immunophenotype was preserved ; the exception was likely secondary to a class switch from IgM to IgG. In 12 of 13 cases, antiidiotypic monoclonal antibodies prepared against the FL reacted with the paired tDL . Analysis of Ig gene rearrangements in four cases by Southern blot hybridization showed evidence of clonal relationships in all cases though concordance was not seen with all probes tested (Ctc, CX, J., PFL1, and PFL2). In the one case that had a discordant L chain rearrangement, sequence analysis of the L chain demonstrated a common mature B cell origin for both the FL and tDL . To determine whether tDL arose from one or more FL cells, the sequences of the H chain variable genes were analyzed. Individual clones of the V region gene of the FL showed a random distribution ofchanges throughout the sequence. In contrast, individual clones of the V region gene from tDL shared numerous nonrandom sequence alterations, implying a common single cell origin. In conclusion, tDL is a mature B cell and arises by transformation of a single FL cell.F ollicular low-grade non-Hodgkin's lymphoma (FL)' has a relatively indolent course with the median survival of 8-10 yr (1, 2) . However, histologic conversion to a more aggressive diffuse lymphoma (DL) is frequently observed at relapse or progression and portends a very poor survival (3, 4) . The actuarial risk of histologic conversion is 44% at 5 yr and 67% at 10 yr (2) . Histologic conversion is not monomorphic, a variety ofintermediate and high grade tumor histologies have been observed . (In this study, lymphomas will be classified according to the Working Formulation ; reference 1.) Antemortem studies suggest that the most common conversion is to diffuse large cell lymphoma (DLCL) (3, 4) though small noncleaved lymphoma (Burkitt's [SNC-B] and nonBurkitt's [SNC-nB]) (4-6) and acute lymphoblastic leukemia (ALL) have been observed (7-9) . A postmortem study (10) of 56 patients initially diagnosed with FL found that the final Abbreviations used in this paper. ALL, acute lymphoblastic leukemia ; DL, diffuse lymphoma; DLCL, diffuse large cell lymphoma; DML, diffuse mixed lymphoma; FL, follicular lymphoma; FLCL, follicular large cell lymphoma ; FML, follicular mixed lymphoma; FSCL, follicular small-cleaved cell lymphoma; LL, lymphoblastic lymphoma ; MBR, major breakpoint cluster region ; SNC-B, small noncleaved Burkitt's lymphoma; SNC-nB, small noncleaved, non-Burkitt's lymphoma ; slg, surface immunoglobulin ; tDL, transformed diffuse lymphoma ; TdT, terminal deoxynucleotidyltransferase. diagnosis was diffuse mixed ...

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Clustering of extensive somatic mutations in the variable region of an immunoglobulin heavy chain gene from a human B cell lymphoma

Cited by 255 publications

References 30 publications

DNA structures at chromosomal translocation sites

DNA structures at chromosomal translocation sites

t(14;18), a journey to eternity

Histologic transformation of follicular lymphoma to diffuse lymphoma represents tumor progression by a single malignant B cell.

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