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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. This Article Full Text (PDF) All Versions of this Article: 2004-02-0749v1 105/8/3303    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Aichberger, K. J Articles by Sillaber, C. Search for Related Content PubMed PubMed Citation Articles by Aichberger, K. J Articles by Sillaber, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 27, 2004 Accepted December 20, 2004 Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): Evidence for cooperative antileukemic effects of STI571 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* Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria Department of Radiation Therapy, Medical University of Vienna, Vienna, Austria Department of Chemistry, Canakkale Onsekiz Mart University, Canakkale, Turkey Institute of Immunology, Medical University of Vienna, Vienna, Austria Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria ISIS Pharmaceuticals Inc., Carlsbad, California, USA Institute of Molecular Pathology (IMP), Vienna, Austria * Corresponding author; email: christian.sillaber{at}meduniwien.ac.at. Anti-apoptotic 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 mcl-1 mRNA and the MCL-1 protein in a constitutive manner. The BCR/ABL-inhibitor 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 MEK-inhibitor PD98059, but not by the PI3-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 (ASO) were applied. The resulting downregulation 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 STI571 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. H. Mak, W. D. Schober, W. Chen, M. Konopleva, J. Cortes, H. M. Kantarjian, M. Andreeff, and B. Z. Carter Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells Mol. Cancer Ther., September 1, 2009; 8(9): 2509 - 2516. [Abstract] [Full Text] [PDF] D. Y. H. 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