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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2507-2516. Prepublished online as a Blood First Edition Paper on November 17, 2005; DOI 10.1182/blood-2005-09-3732. This Article Full Text (PDF) All Versions of this Article: 2005-09-3732v1 107/6/2507    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 Notari, M. Articles by Perrotti, D. Search for Related Content PubMed PubMed Citation Articles by Notari, M. Articles by Perrotti, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 19, 2005 Accepted November 2, 2005 A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation Mario Notari, Paolo Neviani, Ramasamy Santhanam, Blaser W Bradley, Ji-Suk Chang, Annamaria Galietta, Anne E Willis, Denis C Roy, Michael A Caligiuri, Guido Marcucci, and Danilo Perrotti* Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA Division of Hematology/ Oncology, Dept. of Internal Medicine, The Ohio State University, Columbus, Ohio, USA School of Pharmacy, University of Nottingham, Nottingham, United Kingdom Department of Medicine, Maisonneuve-Rosemont Hospital Research Center, Universite de Montreal, Montreal, Quebec, Canada Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA; Division of Hematology/ Oncology, Dept. of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA * Corresponding author; email: danilo.perrotti{at}osumc.edu. Altered mRNA translation is one of the effects exerted by the BCR/ABL oncoprotein in the blast crisis phase of chronic myelogenous leukemia (CML). Here, we report that in BCR/ABL+ cell lines and in patient-derived CML blast crisis mononuclear and CD34+ cells, p210BCR/ABL increases expression and activity of the transcriptional-inducer and translational-regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K or HNRPK) in a dose- and kinase-dependent manner through the activation of the MAPKERK1/2 pathway. Furthermore, HNRPK downregulation and interference with HNRPK translation- but not transcription-regulatory activity impairs cytokine-independent proliferation, clonogenic potential and in vivo leukemogenic activity of BCR/ABL-expressing myeloid 32Dcl3 and/or primary CD34+ CML-BC patient cells. Mechanistically, we demonstrate that decreased IRES (internal ribosome entry site)-dependent Myc mRNA translation accounts for the phenotypic changes induced by inhibition of the BCR/ABL-ERK-dependent HNRPK translation-regulatory function. Accordingly, MYC protein but not mRNA levels are increased in the CD34+ fraction of patients with CML in accelerated and blastic phase but not in chronic phase CML patients and in the CD34+ fraction of marrow cells from healthy donors. Thus, BCR/ABL-dependent enhancement of HNRPK translation-regulation is important for BCR/ABL leukemogenesis and, perhaps, it might contribute to blast crisis transformation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: V. G. Oehler, K. Y. Yeung, Y. E. Choi, R. E. Bumgarner, A. E. Raftery, and J. P. 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