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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3303-3311.
Prepublished online as a Blood First Edition Paper on December 30, 2004; DOI 10.1182/blood-2004-02-0749.
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NEOPLASIA
Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides
Karl J. Aichberger,
Matthias Mayerhofer,
Maria-Theresa Krauth,
Hans Skvara,
Stefan Florian,
Karoline Sonneck,
Cahit Akgul,
Sophia Derdak,
Winfried F. Pickl,
Volker Wacheck,
Edgar Selzer,
Brett P. Monia,
Richard Moriggl,
Peter Valent, and
Christian Sillaber
From the Department of Internal Medicine I, Division of Hematology and Hemostaseology, Department of Radiation Therapy, Institute of Immunology, Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Department of Chemistry, Canakkale Onsekiz Mart University, Canakkale, Turkey; ISIS Pharmaceuticals Inc, Carlsbad, CA; and Institute of Molecular Pathology (IMP), Vienna, Austria.
Antiapoptotic members of the bcl-2 family have recently been implicated in the pathogenesis of chronic myeloid leukemia (CML), a hematopoietic neoplasm associated with the BCR/ABL oncogene. We have examined expression of MCL-1 in primary CML cells and BCR/ABL-transformed cell lines. Independent of the phase of disease, isolated primary CML cells expressed myeloid cell leukemia-1 (mcl-1) mRNA and the MCL-1 protein in a constitutive manner. The BCR/ABL inhibitor imatinib (=STI571) decreased the expression of MCL-1 in these cells. Correspondingly, BCR/ABL enhanced mcl-1 promoter activity, mcl-1 mRNA expression, and the MCL-1 protein in Ba/F3 cells. BCR/ABL-dependent expression of MCL-1 in Ba/F3 cells was counteracted by the mitogen-activated protein-kinase/extracellular signal-regulated kinase (MEK) inhibitor, PD98059, but not by the phosphoinositide 3-kinase inhibitor, LY294002. Identical results were obtained for constitutive expression of MCL-1 in primary CML cells and the CML-derived cell lines K562 and KU812. To investigate the role of MCL-1 as a survival-related target in CML cells, mcl-1 siRNA and mcl-1 antisense oligonucleotides (ASOs) were applied. The resulting down-regulation of MCL-1 was found to be associated with a substantial decrease in viability of K562 cells. Moreover, the mcl-1 ASO was found to synergize with imatinib in producing growth inhibition in these cells. Together, our data identify MCL-1 as a BCR/ABL-dependent survival factor and interesting target in CML. (Blood. 2005;105:3303-3311)
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