| First Author | Collins C | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 27 | Pages | 9899-904 |
| PubMed ID | 24958854 | Mgi Jnum | J:212177 |
| Mgi Id | MGI:5578263 | Doi | 10.1073/pnas.1402238111 |
| Citation | Collins C, et al. (2014) C/EBPalpha is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis. Proc Natl Acad Sci U S A 111(27):9899-904 |
| abstractText | 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/EBPalpha) as a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis. We show that C/EBPalpha is required for the proliferation of Hoxa9/Meis1-transformed cells in culture and that loss of C/EBPalpha 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/EBPalpha, 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/EBPalpha to overcome a block in G1 cell cycle progression. Together, our results suggest a previously unidentified role for C/EBPalpha in maintaining the proliferation required for Hoxa9/Meis1-mediated leukemogenesis. |
