BCL2 translocations in leukemias of mature B cells

Abstract

Although translocations of the BCL2 gene are frequent in B-cell non- Hodgkin's lymphomas (B-NHL) the incidence, nature, and prognostic significance of similar translocations in the phenotypically related chronic leukemias of mature B cells are unknown. Therefore, we examined 170 cases of B-cell chronic lymphocytic leukemia (B-CLL), 7 cases of B- cell prolymphocytic leukemia (B-PLL), 25 cases of hairy cell leukemia (HCL) and 22 cases of splenic lymphoma with villous lymphocytes (SLVL) with defined cytogenetic abnormalities by DNA blot using both 5′ and 3′ BCL2 probes to search for rearrangement of the BCL2 locus. Translocation t(14;18) (q32.3;q21.3) was detected cytogenetically in 3 cases of B-CLL. All had breakpoints in the 3′ region of BCL2, mapping between the major breakpoint region (MBR) and the minor cluster region (mcr), the breakpoint clusters commonly detected in B-NHL. In 2 of the 3 cases, the breakpoint within BCL2 was mapped to a 1.0-kb EcoRI- HindIII fragment indicating a clustering of breakpoints. Two cases of B- CLL had cytogenetically detectable t(2;18)(p11;q21.3) or t(18;22)(q21.3;q11). Both had rearranged the 5′ region of the BCL2 gene to the corresponding lg light-chain gene. Molecular cloning of the t(18;22)(q21.3;q11) showed that the translocation disrupted the BCL2 promoter region and the first untranslated BCL2 exon. Nevertheless, high levels of BCL2 protein were seen in this case. Only 2 other cases in whom cytogenetic analysis was not successful showed rearrangement of the 5′ region of BCL2, an overall incidence of 2.3%. No cases of B-PLL, HCL, or SLVL showed either 5′ or 3′ BCL2 rearrangement. These data confirm the cytogenetic observations that translocations involving the BCL2 locus in all forms of leukemia of mature B cells are rare, and limited to a minor subset of B-CLL. BCL2 translocations in B-CLL involve hot spots of recombination of both the 5′ and 3′ regions of the BCL2 gene, which are distinct from those commonly seen in B-NHL, suggesting distinct pathogenic mechanisms.

Plumbagin reduces chronic lymphocytic leukemia cell survival by downregulation of Bcl-2 but upregulation of the Bax protein level

“…It has been reported that the overexpression of anti-apoptotic proteins such as Bcl-2, Bag-1 and Mcl-1 results in CLL cell accumulation or apoptotic resistance (26,27). In agreement with previous results, the majority of the Chinese CLL patients in the present study showed a high Bcl-2 mRNA, but a slightly low Bax level as determined by qPCR.…”

In vivo monitoring of therapy-induced apoptotic process in patients with chronic lymphocytic leukemia and acute non-lymphoblastic leukemia

“…A chlorambucil induced apoptotic process appeared in analyzed patients with the CLL clinical diagnosis in spite of a high level of immunohistochemically detected protein product bcl 2 gene. Our results confirmed the numerous experimental studies of many authors that the high and constant expression of bcl 2 gene in CLL cells excludes the pathogenic role of bcl 2 oncogene in the development of clones of neoplastic cells (23)(24)(25). Bcl 2 and bax interaction, rather than the absolute level of bcl 2 expression, is more important determinant of CLL cell apoptosis (26).…”

In leukaemic CD5+ B cells the expression of BCL‐2 gene family is shifted toward protection from apoptosis

“…B-CLL CD5 cells which contain a t(14;18) translocation thus indicating Bcl-2 over-expression Hanada et al, 1993). Bcl-2 levels in B-CLL do not reflect a rearrangement of Bcl-2 gene, which appears to be a rare event in CLL cells (Adachi et al, 1989;Raghobier et al, 1991;Dyer et al, 1994), and can be modulated by B-cell activators and cytokines .…”