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 Blood, 1 October 2006, Vol. 108, No. 7, pp. 2416-2419.
Prepublished online as a Blood First Edition Paper on June 20, 2006; DOI 10.1182/blood-2006-02-003582.

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NEOPLASIA
Brief report

CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but differ in their antileukemic activities

Young-Jin Lee, Letetia C. Jones, Nikolai A. Timchenko, Danilo Perrotti, Daniel G. Tenen, and Scott C. Kogan

From the Department of Laboratory Medicine and Comprehensive Cancer Center, University of California San Francisco; Huffington Center on Aging and Department of Pathology, Baylor College of Medicine, Houston, TX; Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus; and Harvard Institutes of Medicine, Harvard Medical School, Boston, MA.

CCAAT/enhancer binding proteins (C/EBPs) play critical roles in myelopoiesis. Dysregulation of these proteins likely contributes to the pathogenesis of myeloid disorders characterized by a block in granulopoiesis. In one such disease, acute promyelocytic leukemia (APL), a promyelocytic leukemia–retinoic acid receptor {alpha} (PML-RAR{alpha}) fusion protein is expressed as a result of a t(15;17) chromosomal translocation. Treatment of PML-RAR{alpha} leukemic cells with all-trans retinoic acid (ATRA) causes them to differentiate into mature neutrophils, an effect thought to be mediated by C/EBPs. In this study, we assess the potential for cooperativity between increased C/EBP activity and ATRA therapy. We demonstrate that although both C/EBP{alpha} and C/EBP{epsilon} can significantly prolong survival in a mouse model of APL, they are not functionally equivalent in this capacity. We also show that forced expression of C/EBP{alpha} or C/EBP{epsilon} in combination with ATRA treatment has a synergistic effect on survival of leukemic mice compared with either therapy alone.


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