C/EBP? is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis.

ABSTRACT: Homeobox A9 (HOXA9) is a homeodomain-containing transcription factor that plays a key role in hematopoietic stem cell expansion and is commonly deregulated in human acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia (AML) lead to overexpression of HOXA9, almost always in association with overexpression of its cofactor meis homeobox 1 (MEIS1) . A wide range of data suggests that HOXA9 and MEIS1 play a synergistic causative role in AML, although the molecular mechanisms leading to transformation by HOXA9 and MEIS1 remain elusive. In this study, we identify CCAAT/enhancer binding protein alpha (C/EBP?) as a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis. We show that C/EBP? is required for the proliferation of Hoxa9/Meis1-transformed cells in culture and that loss of C/EBP? greatly improves survival in both primary and secondary murine models of Hoxa9/Meis1-induced leukemia. Over 50% of Hoxa9 genome-wide binding sites are cobound by C/EBP?, which coregulates a number of downstream target genes involved in the regulation of cell proliferation and differentiation. Finally, we show that Hoxa9 represses the locus of the cyclin-dependent kinase inhibitors Cdkn2a/b in concert with C/EBP? to overcome a block in G1 cell cycle progression. Together, our results suggest a previously unidentified role for C/EBP? in maintaining the proliferation required for Hoxa9/Meis1-mediated leukemogenesis.

SUBMITTER: Collins C 

PROVIDER: S-EPMC4103350 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature