C-Abl Regulates Mcl-1 Gene Expression In Chronic Lymphocytic Leukaemia Cells

Abstract 3579

Chronic lymphocytic leukaemia (CLL) is a prevalent malignancy characterised by the clonal expansion of mature B cells that are resistant to apoptosis. This resistance to apoptosis will partly be due to Mcl-1 expression because high levels of this protein in CLL cells correlate with poor disease prognosis and resistance to chemotherapy. Thus, understanding the mechanism(s) regulating Mcl-1 expression in CLL cells may be useful in the development of new therapies for this incurable disease. In the present study we show a strong relationship between c-Abl and Mcl-1 expression in CLL cells. We show that treatment of CLL cells with Abl-specific siRNA or with imatinib, to inhibit c-Abl activity, results in the downregulation of Mcl-1 protein and mRNA. A major regulator of Mcl-1 gene expression is STAT3. Our data show that CLL cells expressing high levels of c-Abl also show elevated levels of phospho-STAT3, and that STAT3 phosphorylation in CLL cells is dependent on c-Abl activity. However, STAT3 phosphorylation by c-Abl is not direct, and requires activation of NFkB, secretion of autocrine IL6 and active PKC. Taken together, our results provide clearer definition of the pathobiological role of c-Abl in CLL cells. Given that high NFkB activation, plasma IL6 levels and Mcl-1 all correlate with poor disease prognosis in CLL, our work potentially connects several features of CLL cells that are important to their pathophysiology by suggesting a central role of c-Abl in their regulation. Since CLL cells expressing high levels of c-Abl and Mcl-1 belong to the unmutated, poor prognostic group of CLL, c-Abl inhibition may have therapeutic application in the treatment of this disease, especially for those patients who are resistant to conventional chemotherapeutic agents.