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

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BlankBlood, 24 February 2011, Vol. 117, No. 8, pp. 2414-2422.

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

C. 1, Fatima Talab1, Mirko Zuzel1, Ke Lin1,2,*, and ph R.

Slupsky1,*

1 Division of Haematology, Liverpool Cancer Research UK Centre, University of

Liverpool, Liverpool, United Kingdom; and 2 Department of Haematology, Royal

Liverpool University Hospital, Liverpool, United Kingdom

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-(kappa)B, 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.