Submitted September 26, 2007
Accepted May 24, 2008
Transcriptional repression of c-Myb and GATA-2 is involved in the biological effects of C/EBP
in p210 BCR/ABL-expressing cells
Angela Rachele Soliera, Maria Rosa Lidonnici, Giovanna Ferrari-Amorotti, Marco Prisco, Ying Zhang, Robert V Martinez, Nick J Donato, and Bruno Calabretta*
Department of Cancer Biology, Thomas Jefferson Medical College, Philadelphia, PA, United States
Department of Biomedical Sciences, University of Modena Medical School, Modena, Italy
Wyeth Genetics Institute, Wyeth Genetics Institute, Cambridge, MA, United States
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, United States
* Corresponding author; email: b_calabretta{at}mail.jci.tju.edu.
Levels of C/EBP
are low in myeloid blast crisis of chronic myelogenous leukemia and its expression in p210BCR/ABL-expressing hematopoietic cells induces granulocytic differentiation, inhibits proliferation and suppresses leukemogenesis. To assess the underlying mechanisms, C/EBP targets were identified by microarray analyses. Upon C/EBP activation, expression of c-Myb and GATA-2 was repressed in 32D-BCR/ABL, K562 and CML-BC primary cells but only c-Myb levels decreased slightly in CD34+ normal progenitors. The role of these two genes for the effects of C/EBP was assessed by perturbing their expression in K562 cells. Expression of c-Myb blocked the proliferation inhibition and differentiation-inducing effects of C/EBP while c-Myb siRNA treatment enhanced C/EBP-mediated proliferation inhibition and induced changes in gene expression indicative of monocytic differentiation. GATA-2 expression suppressed the proliferation inhibitory effect of C/EBP but blocked in part the effect on differentiation; GATA-2 siRNA treatment had no effects on C/EBP induction of differentiation but inhibited proliferation of K562 cells, alone or upon C/EBP activation. In summary, the effects of C/EBP in p210BCR/ABL-expressing cells depend, in part, on transcriptional repression of c-Myb and GATA-2. Since perturbation of c-Myb and GATA-2 expression has non identical consequences for proliferation and differentiation of K562 cells, the effects of C/EBP appear to involve different transcription-regulated targets.
