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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.

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NEOPLASIA

CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer–binding protein alpha

Steffen Koschmieder1, Francesco D'Alò2, Hanna Radomska3, Christine Schöneich1, Ji Suk Chang4, Marina Konopleva5, Susumu Kobayashi3, Elena Levantini3, Nanjoo Suh6, Annalisa Di Ruscio2, Maria Teresa Voso2, Julie C. Watt5, Ramasamy Santhanam4, Bülent Sargin1, Hagop Kantarjian5, Michael Andreeff5, Michael B. Sporn7, Danilo Perrotti4, Wolfgang E. Berdel1, Carsten Müller-Tidow1, Hubert Serve1, and Daniel G. Tenen3

1 Department of Medicine, Hematology and Oncology, University of Münster, Münster Germany; 2 Istituto di Ematologia, Università Cattolica del Sacro Cuore, Rome, Italy; 3 Harvard Institutes of Medicine and Beth Israel Deaconess Medical Center, Boston, MA; 4 Human Cancer Genetics Program, The Ohio State University Medical Center, Columbus; 5 The University of Texas M. D. Anderson Cancer Center, Houston; 6 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway; and 7 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH

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 apoptosis 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 up-regulation is required for CDDO-induced granulocytic differentiation and depends on the integrity of the CEBPA upstream open reading frame (uORF). Moreover, CDDO increases the ratio of transcriptionally active p42 and the inactive p30 CEBPA isoform, which, in turn, leads to transcriptional activation of CEBPA-regulated genes (eg, GSCFR) and is associated with dephosphorylation of eIF2{alpha} 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.


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