Submitted February 14, 2006
Accepted May 28, 2006
CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but they differ in their anti-leukemic activities
Young-Jin Lee, Letetia C Jones, Nikolai A Timchenko, Danilo Perrotti, Daniel G Tenen, and Scott C Kogan*
Wonkwang University School of Medicine, Iksan, Chonbuk, South Korea
University of California, San Francisco
Baylor College of Medicine, Houston, TX
The Ohio State University, Columbus, OH
Harvard Institutes of Medicine, Harvard Medical School, Boston, MA
Department of Laboratory Medicine and Comprehensive Cancer Center, University of California San Fran
* Corresponding author; email: scott.kogan{at}ucsf.edu.
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 
(PML-RAR) fusion protein is expressed as a result of a t(15,17) chromosomal translocation. Treatment of PML-RAR 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 and C/EBP
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 or C/EBP in combination with ATRA treatment has a synergistic effect on survival of leukemic mice compared to either therapy alone.
