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Blood, 1 August 2007, Vol. 110, No. 3, pp. 994-1003. Prepublished online as a Blood First Edition Paper on May 2, 2007; DOI 10.1182/blood-2007-03-078303. This Article Full Text (PDF) All Versions of this Article: blood-2007-03-078303v1 110/3/994    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 Chang, J. S. Articles by Perrotti, D. Search for Related Content PubMed PubMed Citation Articles by Chang, J. S. Articles by Perrotti, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 5, 2007 Accepted April 24, 2007 High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP E2-dependent suppression of C/EBP-driven Myeloid Differentiation Ji Suk Chang, Ramasamy Santhanam, Rossana Trotta, Paolo Neviani, Anna M Eiring, Edward Briercheck, Mattia Ronchetti, Denis C. Roy, Bruno Calabretta, Michael A. Caligiuri, and Danilo Perrotti* Department of Microbiology Virology and Medical Genetics, Human Cancer Genetics Program and The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA, United States Division of Hematology-Immunology, Maisonneuve-Rosemont Hospital Research Center, Montreal, Canada * Corresponding author; email: danilo.perrotti{at}osumc.edu. The inability of myeloid chronic myelogenous leukemia blast crisis (CML-BC) progenitors to undergo neutrophil differentiation depends on suppression of C/EBP expression through the translation inhibitory activity of the RNA binding protein hnRNP E2. Here we show that "oncogene dosage" is a determinant factor for suppression of differentiation in CML-BC. In fact, high levels of p210-BCR/ABL are required for enhanced hnRNP E2 expression, which depends on phosphorylation of hnRNP E2 serines 173, 189, 272 and threonine 213 by the BCR/ABL-activated MAPKERK1/2. Serine/threonine to alanine substitution abolishes hnRNP E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Similarly, pharmacologic inhibition of MAPKERK1/2 activity decreases hnRNP E2 binding to the 5'UTR of C/EBP mRNA by impairing hnRNP E2 phosphorylation and stability. This, in turn, restores in vitro and/or in vivo C/EBP expression and G-CSF-driven neutrophilic maturation of differentiation-arrested BCR/ABL+ cell lines, primary CML-BCCD34+ patient-cells and lineage-negative mouse bone marrow cells expressing high levels of p210-BCR/ABL. Thus, increased BCR/ABL oncogenic tyrosine kinase activity is essential for suppression of myeloid differentiation of CML-BC progenitors as it is required for sustained activation of the MAPKERK1/2-hnRNP E2-C/EBP differentiation-inhibitory pathway. Furthermore, these findings suggest the inclusion of clinically-relevant MAPK inhibitors in the therapy of CML-BC. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Gao, A. Howard, K. Ban, and J. Chandra Oxidative Stress Promotes Transcriptional Up-regulation of Fyn in BCR-ABL1-expressing Cells J. Biol. Chem., March 13, 2009; 284(11): 7114 - 7125. [Abstract] [Full Text] [PDF] S. Koschmieder, B. Halmos, E. Levantini, and D. G. Tenen Dysregulation of the C/EBP{alpha} Differentiation Pathway in Human Cancer J. Clin. Oncol., February 1, 2009; 27(4): 619 - 628. [Abstract] [Full Text] [PDF] A. R. Soliera, M. R. Lidonnici, G. Ferrari-Amorotti, M. Prisco, Y. Zhang, R. V. Martinez, N. J. Donato, and B. Calabretta Transcriptional repression of c-Myb and GATA-2 is involved in the biologic effects of C/EBP{alpha} in p210BCR/ABL-expressing cells Blood, September 1, 2008; 112(5): 1942 - 1950. [Abstract] [Full Text] [PDF] A. M. Eiring, P. Neviani, R. Santhanam, J. J. Oaks, J. S. Chang, M. Notari, W. Willis, C. Gambacorti-Passerini, S. Volinia, G. Marcucci, et al. Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis Blood, January 15, 2008; 111(2): 816 - 828. [Abstract] [Full Text] [PDF] C. H. Jamieson Chronic Myeloid Leukemia Stem Cells Hematology, January 1, 2008; 2008(1): 436 - 442. [Abstract] [Full Text] [PDF] S. Koschmieder, F. D'Alo, H. Radomska, C. Schoneich, J. S. Chang, M. Konopleva, S. Kobayashi, E. Levantini, N. Suh, A. Di Ruscio, et al. CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha Blood, November 15, 2007; 110(10): 3695 - 3705. [Abstract] [Full Text] [PDF] J. P. Radich The Biology of CML Blast Crisis Hematology, January 1, 2007; 2007(1): 384 - 391. [Abstract] [Full Text] [PDF]

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