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

Abstract

This study further investigated the mechanisms that control apoptosis in leukaemic CD5+ B cells, and focused on the Bcl-2 gene family. The pattern of expression of Bcl-2, Bcl-xL, Bcl-xS and Bax genes, selected because of their interrelated role in the control of apoptosis, was analysed in a series of CD5+ B-cell chronic lymphoid leukaemias. Cells from 34 patients with chronic lymphoid leukaemia of B-cell type (23 B-chronic lymphocytic leukaemia (B-CLL) and 11 mantle cell lymphoma (MCL) in leukaemic phase) were investigated. High levels of Bcl-2 mRNA were observed by Northern blot and high levels of Bcl-2 protein were detected by cytofluorograph analysis with a specific monoclonal antibody (MAb) in all cases. Strong Bax expression was detected by RT-PCR in 20/23 B-CLL cases; Bax was also observed in 8/11 MCL in leukaemic phase with variable degree of intensity. In both B-CLL and MCL samples the presence of Bax protein was confirmed by cytofluorograph analysis. RT-PCR detected high levels of Bcl-xL in 16/23 B-CLL and in 8/11 MCL in leukaemic phase, whereas Bcl-xS was detectable in low to trace amounts respectively in 13/23 B-CLL and in 6/11 MCL in leukaemic phase. According to the functional role of Bcl-2, Bcl-xL, Bcl-xS and Bax, these data indicate that the pattern of Bcl-2 family genes expression in leukaemic CD5+ B cells is skewed toward prevention of apoptosis and may thus favour the relentless accumulation of CD5+ leukaemic B cells.

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

“…Moreover, low levels of sCD23 and β2M, known markers of disease activity in CLL, were correlated with higher apoptosis levels, 28 although previously published studies did not find any significant association between some apoptosis regulation proteins such as bcl-2, mcl-1 and Rai stages, while their correlation with CD23 or β2M was not investigated. [29][30][31][32] Most of these studies involved a small number of patients and methods other than flow cytometry, such as Western blotting, immunoblotting and PCR. 33 However, Kitada et al 32 demonstrated that high bcl-2/bax ratio was associated with elevated white blood cell count, similar to that found in our series.…”

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

“…1 The apoptotic resistance of CLL cells has been attributed, in part, to high expression of antiapoptotic proteins such as Bcl-2, Bcl-X L , and Mcl-1. [2][3][4][5][6][7][8] Our previous work demonstrated that CLL cells contain multiple mitochondrial defects including mtDNA mutations, aberrant mitochondrial biogenesis, and increased generation of the oxygen radical superoxide, which is predominantly produced in the mitochondria. These abnormalities are associated with alterations in sensitivity to anticancer agents, suggesting that they may compromise the execution of the mitochondrial apoptotic machinery.…”

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

“…178,179 Other genes regulating apoptosis, such as Bcl-2, Bcl-X/L, Mcl-1 or Bag-1, have been suggested to influence sensitivity to NA, although the results remain controversial. [180][181][182][183][184][185][186][187] Alterations in p53 function have been related to in vitro Leukemia resistance to NA. 68,188 p53 appears to have a specific role in resistance to NA since it possesses exonuclease activity, and may therefore be able to excise illegally DNA-incorporated NA.…”