title: c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells.
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.
authors.affiliation: Division of Haematology, Liverpool Cancer Research UK Centre, University of Liverpool, Daulby Street, Liverpool, UK. jcallen@liverpool.ac.uk
authors.forename: John C
authors.initials: JC
authors.lastname: Allen
authors.forename: Fatima
authors.initials: F
authors.lastname: Talab
authors.forename: Mirko
authors.initials: M
authors.lastname: Zuzel
authors.forename: Ke
authors.initials: K
authors.lastname: Lin
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Slupsky
mesh_terms: D001549:Benzamides; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl