BCL2 translocations in leukemias of mature B cells

Dyer, MJ; Zani, VJ; Lu, WZ; O'Byrne, A; Mould, S; Chapman, Robert M.; Heward, JM; Kayano, Hidekazu; Jadayel, D; Matutes, Estella

doi:10.1182/blood.v83.12.3682.3682

Cited by 99 publications

(10 citation statements)

References 39 publications

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“…5%) (Raghoebier et al, 1991), 4/170 (2 . 3%) (Dyer et al, 1994). In our study the frequency of vcr rearrangements was 8/67 (12%).…”

Section: Discussionsupporting

confidence: 51%

“…In B-CLL the bcl-2 gene is preferentially juxtaposed to Ig or k genes. In earlier studies, variant bcl-2 translocation were described in 10% of B-CLL (Adachi et al, 1989(Adachi et al, , 1990, but in later studies the frequency has been lower (Dyer et al, 1994). A variant translocation has also been described in a case of follicular lymphoma (Bertheas et al, 1991).…”

mentioning

confidence: 94%

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Bcl‐2 rearrangements with breakpoints in both vcr and mbr in non‐Hodgkin’s lymphomas and chronic lymphocytic leukaemia

Merup¹,

Spasokoukotskaja

Einhorn

et al. 1996

Br J Haematol

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The bcl-2 gene is rearranged in most cases of follicular lymphoma and the breakpoint clusters into two specific regions: mbr and mcr. Rearrangements to immunoglobulin heavy chain genes (IgH) result in a deregulation of the gene and increased transcription of mRNA for the bcl-2 protein. In chronic lymphocytic leukaemia (CLL) expression of bcl-2 protein is increased but rearrangement of the gene can be found only in a minority of cases: commonly a variant translocation with a breakpoint region located 5' of the bcl-2 gene (vcr) with preferential rearrangement to immunoglobulin light chain genes. We have analysed breakpoints in mbr and vcr in malignant cells from 96 patients with B-CLL, 45 with hairy cell leukaemia (HCL) and 41 with high- and low-grade non-Hodgkin's lymphomas (NHL). Vcr rearrangements were observed in nine patients (12%) with B-CLL. Four patients had co-migration of rearranged bcl-2 bands to kappa genes and two patients to IgH. Cytogenetic abnormalities involving 18q21, the site of the bcl-2 gene, was found in two cases only. In several cases with bcl-2 gene rearrangement chromosomal aberrations not including 18q21 were observed. In six patients (two B-CLL, one follicular lymphoma, one immunocytoma and two high-grade lymphomas), breakpoints in both vcr and mbr were found. In HCL a rearrangement in the vcr region was found in one case. Bcl-2 protein immunostaining of B-CLL showed intense bcl-2 expression in all cases and no correlation was found between gene rearrangement and protein expression. Our study confirms that breakpoints in the bcl-2 gene commonly cluster to the vcr region in B-CLL, but in most cases over-expression of bcl-2 protein has to be explained by other mechanisms than bcl-2 gene rearrangement. We also report that simultaneous breakpoints in mbr and vcr is a recurrent phenomenon in B-CLL and in other high- and low-grade non-Hodgkin's lymphomas.

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“…5%) (Raghoebier et al, 1991), 4/170 (2 . 3%) (Dyer et al, 1994). In our study the frequency of vcr rearrangements was 8/67 (12%).…”

Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 94%

Bcl‐2 rearrangements with breakpoints in both vcr and mbr in non‐Hodgkin’s lymphomas and chronic lymphocytic leukaemia

Merup¹,

Spasokoukotskaja

Einhorn

et al. 1996

Br J Haematol

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“…Thus, Bcl-2 is overexpressed in CLL (53,54) and it has been suggested that Bcl-2 overexpression may influence survival, while it does not correlate with clinical staging (55). In contrast to fol-licular lymphoma, however, the t(14;18) which leads to the rearrangement of Bcl-2 with the Ig heavy chain gene is extremely rare in CLL (56). Although the expression of the various family proteins is variable in CLL, the overall pattern favors inhibition of apoptosis.…”

Section: Other Markers Expressed In Cll With Clinical/prognostic And/mentioning

confidence: 99%

Morphological and Immunophenotypic Features of Chronic Lymphocytic Leukemia

Matutes

Polliack²

2000

Rev Clin Exp Hematol

109

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In this review, we summarize the morphological features and immunophenotypic profile of chronic lymphocytic leukemia (CLL) cells, discuss the value of these investigations as front line diagnostic tests, and emphasize their correlation with the clinical features, disease progression, molecular genetics and pathogenesis of CLL. In CLL, the morphology of the circulating cells is characteristic and typical in the majority of cases. However, 15% of patients, either at diagnosis or during the course of the disease, show atypical morphology reflected by either (1) an increased (> 10%) number of circulating prolymphocytes, designated CLL/PL, or (2) an increased (> 15%) number of circulating lymphoplasmacytic and cleaved cells, designated 'atypical' CLL. There is strong evidence of a close association between atypical morphology (CLL/PL) and atypical (CLL) and clinical features, e.g. disease progression, advanced stage and survival, molecular genetics, particularly trisomy 12, but also the rare cases with t(11;14) or t(14;19), p53 abnormalities, unmutated immunoglobulin (Ig) VH genes and origin of the cell (naive, pregerminal center cell). CLL cells have a distinct immunological repertoire different from that of other lymphoproliferative disorders. The typical CLL phenotype is CD5+, CD23+, FMC7-, weak expression of surface Ig (sIg) and weak or absent expression of membrane CD22 and CD79b. The latter marker identifies an extracellular epitope of the B-cell receptor (BCR) beta chain and its weak or absent expression in CLL may derive from the expression of a truncated form. This, together with the low expression of CD22, might explain the abnormal signal transduction of CLL cells similar to that of anergic B lymphocytes. Because no single marker is specific for CLL, a composite phenotype considering this set of 5 or 6 markers compounded into a scoring system helps to distinguish CLL from the other B-cell malignancies. Immunophenotypic analysis has also been shown to be useful for minimal residual disease detection and adds valuable prognostic information because the expression of certain markers, such as FMC7 or CD38, seems to be associated with a poor outcome. In addition, CLL cells express a variety of Bcl-2 family proteins with a profile that favors inhibition of apoptosis which, together with the interaction with microenvironmental (e.g. stromal) cells and the release of cytokines, explains the long life span and subsequent accumulation of CLL cells in various organs. Despite controversies relating to the expression of adhesion molecules (selectins and integrins) in CLL cells, it appears that some of these molecules do play a role in the pathogenesis, biology and clinical patterns of the disease. In conclusion, morphology and immunophenotype are the two essential investigations, which must be carried out in all cases of CLL. Both provide relevant information in terms of diagnosis, course of the disease, prognosis and pathogenesis.

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“…Evidence for an involvement of other genetic regions in rare cases of CLL has come from chromosome banding and CGH studies. These aberrations are often gains of chromosomal regions, genetic studies, Bcl-2 rearrangements only very rarely occurred in CLL (96,115,(121)(122)(123). From another rearrangement involving the IgH locus, the t(14;19)(q32;q13), the Bcl-3 gene was cloned (37,38,(124)(125)(126)(127).…”

Section: Trisomy 3q Trisomy 8q Deletion 9pmentioning

confidence: 99%

Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

Stilgenbauer

Lichter

Döhner

2000

Rev Clin Exp Hematol

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The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently affected genomic regions, the search for candidate genes is ongoing. In parallel, the accurate evaluation of the incidence of chromosome aberrations in CLL by FISH allows the correlation of genetic abnormalities with clinical disease manifestations and outcome. In particular, 17p abnormalities and deletions in 11q22-q23 have already been shown to be among the most important independent prognostic factors identifying subgroups of patients with rapid disease progression and short survival. In addition, deletion 17p has been associated with resistance to treatment with purine analogs. Therefore, genetic abnormalities may allow a risk assessment for individual patients at the time of diagnosis, thus giving the opportunity for a risk-adapted management.

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BCL2 translocations in leukemias of mature B cells

Cited by 99 publications

References 39 publications

Bcl‐2 rearrangements with breakpoints in both vcr and mbr in non‐Hodgkin’s lymphomas and chronic lymphocytic leukaemia

Bcl‐2 rearrangements with breakpoints in both vcr and mbr in non‐Hodgkin’s lymphomas and chronic lymphocytic leukaemia

Morphological and Immunophenotypic Features of Chronic Lymphocytic Leukemia

Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

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