Blood Journal
Leading the way in experimental and clinical research in hematology

c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells

  1. John C. Allen1,
  2. Fatima Talab1,
  3. Mirko Zuzel1,
  4. Ke Lin1,2,*, and
  5. Joseph R. Slupsky1,*
  1. 1Division of Haematology, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, United Kingdom; and
  2. 2Department of Haematology, Royal Liverpool University Hospital, Liverpool, United Kingdom

Abstract

Chronic lymphocytic leukemia (CLL) is a malignancy characterized by clonal expansion of mature B cells that are resistant to apoptosis. This resistance to apoptosis partly results from 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 down-regulation 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 requires activation of nuclear factor-κB, secretion of autocrine interleukin-6, and active protein kinase C. Taken together, our data demonstrate the mechanism involved in c-Abl regulation of Mcl-1 expression in CLL cells, and suggest that c-Abl inhibition has therapeutic application in the treatment of this disease.

  • Submitted August 9, 2010.
  • Accepted December 12, 2010.
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