CD5-induced apoptosis of B cells in some patients with chronic lymphocytic leukemia

Institut de Synergie des Sciences et de la Santé, Brest University Medical School, Brest, France.
Leukemia (Impact Factor: 10.43). 02/2002; 16(1):44-52. DOI: 10.1038/sj.leu.2402327
Source: PubMed


Although B chronic lymphocytic leukemia (B-CLL) is characterized by prolonged survival of CD5(+) B cells in vivo, these cells apoptose spontaneously in vitro. The effect of CD5 ligation on apoptosis was studied in 27 newly diagnosed patients with B-CLL, in relation to the expression of surface IgM (sIgM), CD79b, CD38, CD72 and CD19. B cells from 15 patients (group I) were resistant to anti-CD5-induced apoptosis, whereas apoptosis above spontaneous levels was seen in the remaining 12 studied (group II). Group II was then subdivided on the basis of differences in the time required to reach maximum apoptosis: whilst B cells from seven patients underwent apoptosis by 18 h, those from the remaining five needed 36 h to apoptose. The expression of sIgM, CD5, CD79b and CD38 was higher in group II than group I, suggesting that signaling for apoptosis might operate via CD79, and that CD38 expression was required. As shown by flow cytometry and confirmed by Western blotting, apoptosis was associated with a decrease in the ratios of Bcl-2/Bax and Bcl(XL)/Bax, due to an increase in the level of Bax, but no change in that of Bcl-2. This heterogeneous apoptotic response to CD5 ligation offers an explanation for the incomplete success of anti-CD5 monoclonal therapy, and might help identify patients who would respond to such treatment.

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Available from: Pierre Youinou, Mar 19, 2014
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    • "However, clinical benefits were limited or of short in duration. More recently, it was demonstrated that, in vitro, an anti-CD5 mAb can induce apoptosis of B cells from some patients with CLL and that cross-linking of CD5 on the surface of the cells was essential for apoptosis induction [9,10]. "
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    ABSTRACT: The increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells. The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5. Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential.
    Molecular Cancer 04/2011; 10(1):42. DOI:10.1186/1476-4598-10-42 · 4.26 Impact Factor
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    • "In B-CLL there are few studies to date which have addressed the possible role of CD5 molecule in activation or proliferation processes, the activation of A-SMase has been shown to occur after CD5 cross-linking [25], as well as the induction of IL-2 and a discrete proliferation of leukaemic B cells [26]. In contrast, the majority of works have reported CD5-induced apoptosis in these lymphoproliferative disease [27] [28] [29]. There are few data concerning CD5-signalling pathway in B-CLL, but recently Renaudineau et al. [30] have proposed that signals from CD5 could be transduced via CD79 in the vicinity of the BCR. "
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    ABSTRACT: B-chronic lymphocytic leukaemia (B-CLL) is a heterogeneous disease characterized by an accumulation of B lymphocytes expressing CD5. To date, the biological significance of this molecule in B-CLL B cells remains to be elucidated. In this study, we have analysed the functional consequences of the binding of an anti-CD5 antibody on B-CLL B cells. To this purpose, we have measured the percentage of viability of B-CLL B cells in the presence or in the absence of anti-CD5 antibodies and also examined some of the biochemical events downstream the CD5-signalling. We demonstrate that anti-CD5 induces phosphorylation of protein tyrosine kinases and protein kinase C (PKC), while no activation of Akt/PKB and MAPKs is detected. This signalling cascade results in viability in a group of patients in which we observe an increase of Mcl-1 levels, whereas the levels of bcl-2, bcl-x(L) and XIAP do not change. We also report that this pathway leads to IL-10 production, an immunoregulatory cytokine that might act as an autocrine growth factor for leukaemic B cells. Inhibition of PKC prevents the induction of Mcl-1 and IL-10, suggesting that the activation of PKC plays an important role in the CD5-mediated survival signals in B cells from a subset of B-CLL patients.
    Leukemia Research 03/2007; 31(2):183-93. DOI:10.1016/j.leukres.2006.03.021 · 2.35 Impact Factor
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    ABSTRACT: The mutational status of tumor immunoglobulin V(H) genes is providing a powerful prognostic marker for chronic lymphocytic leukemia (CLL), with patients having tumors expressing unmutated V(H) genes being in a less favorable subset. However, the biologic differences correlating with V(H) gene status that could determine the clinical course of the disease are unknown. Here we show that differing responses to IgM ligation are closely associated with V(H) gene status. Specifically, 80% of cases with unmutated V(H) genes showed increased global tyrosine phosphorylation following IgM ligation, whereas only 20% of samples with mutated V(H) genes responded (P =.0002). There was also an association between response to IgM ligation and expression of CD38 (P =.015). The Syk kinase, critical for transducing B-cell receptor (BCR)- derived signals, was constitutively present in all CLL samples, and there was a perfect association between global phosphorylation and induction of phosphorylation/activation of Syk. Nonresponsiveness to anti-IgM could be circumvented by ligation of IgD (10 of 15 samples tested) or the BCR-associated molecule CD79alpha (12 of 15 samples tested). These results suggest that multiple mechanisms underlie nonresponsiveness to anti-IgM in CLL and that retained responsiveness to anti-IgM contributes to the poor prognosis associated with the unmutated subset of CLL. The prognostic power of the in vitro response to IgM ligation remains to be determined in a large series, but the simple technology involved may present an alternative or additional test for predicting clinical course.
    Blood 03/2003; 101(3):1087-93. DOI:10.1182/blood-2002-06-1822 · 10.45 Impact Factor
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