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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3695-3705. Prepublished online as a Blood First Edition Paper on August 1, 2007; DOI 10.1182/blood-2006-11-058941. This Article Full Text (PDF) Supplemental Table All Versions of this Article: blood-2006-11-058941v1 110/10/3695    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 Koschmieder, S. Articles by Tenen, D. G. Search for Related Content PubMed PubMed Citation Articles by Koschmieder, S. Articles by Tenen, D. G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 21, 2006 Accepted July 25, 2007 CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational upregulation of p42 CCAAT enhancer binding protein alpha Steffen Koschmieder*, Francesco D'Alo, Hanna Radomska, Christine Schoneich, Ji Suk Chang, Marina Konopleva, Susumu Kobayashi, Elena Levantini, Nanjoo Suh, Annalisa Di Ruscio, Maria Teresa Voso, Julie C. Watt, Ramasamy Santhanam, Bulent Sargin, Hagop Kantarjian, Michael Andreeff, Michael B. Sporn, Danilo Perrotti, Wolfgang E. Berdel, Carsten Muller-Tidow, Hubert Serve, and Daniel G. Tenen Department of Medicine, Hematology and Oncology, University of Munster, Munster, Germany Istituto di Ematologia, Universita' Cattolica del Sacro Cuore, Rome, Italy Department of Hematology/Oncology, Harvard Institutes of Medicine and Beth Israel Deaconess Medical Center, Boston, MA, United States Human Cancer Genetics Program, The Ohio State University Medical Center, Columbus, OH, United States Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, United States Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, United States * Corresponding author; email: steffen.koschmieder{at}ukmuenster.de. 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis of tumor cells in vitro and in vivo. Here we assessed the effects of CDDO on CCAAT enhancer binding protein alpha (CEBPA), a transcription factor critical for granulocytic differentiation. In HL60 acute myeloid leukemia (AML) cells, CDDO (0.01 to 2 µM) induces apoptotis in a dose-dependent manner. Conversely, subapoptotic doses of CDDO promote phagocytic activity and granulocytic-monocytic differentiation of HL60 cells through increased de novo synthesis of p42 CEBPA protein. CEBPA translational upregulation is required for CDDO-induced granulocytic differentiation and depends on the integrity of the CEBPA upstream open reading frame (uORF). Moreover, CDDO in-creases the ratio of transcriptionally active p42 and the inactive p30 CEBPA isoform which, in turn, leads to transcriptional activation of CEBPA-regulated genes (e.g GSCFR) and is associated with dephosphorylation of eIF2 and phosphorylation of eIF4E. In concordance with these results, CDDO induces a CEBPA ratio change and differentiation of primary blasts from patients with acute myeloid leukemia (AML). Because AML is characterized by arrested differentiation, our data suggest the inclusion of CDDO in the therapy of AML characterized by dysfunctional CEBPA expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Pabst and B. U. Mueller Complexity of CEBPA Dysregulation in Human Acute Myeloid Leukemia Clin. Cancer Res., September 1, 2009; 15(17): 5303 - 5307. [Abstract] [Full Text] [PDF] P. A. Ho, T. A. Alonzo, R. B. Gerbing, J. Pollard, D. L. Stirewalt, C. Hurwitz, N. A. Heerema, B. Hirsch, S. C. Raimondi, B. Lange, et al. Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group Blood, June 25, 2009; 113(26): 6558 - 6566. [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] T. Motiwala, S. Majumder, K. Ghoshal, H. Kutay, J. Datta, S. Roy, D. M. Lucas, and S. T. Jacob PTPROt Inactivates the Oncogenic Fusion Protein BCR/ABL and Suppresses Transformation of K562 Cells J. Biol. Chem., January 2, 2009; 284(1): 455 - 464. [Abstract] [Full Text] [PDF]

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