C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 27; pp. 9899 - 9904
• Main Authors: Collins, Cailin, Wang, Jingya, Miao, Hongzhi, Bronstein, Joel, Nawer, Humaira, Xu, Tao, Figueroa, Maria, Muntean, Andrew G., Hess, Jay L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.07.2014; National Acad Sciences
• Subjects: animal models; Animals; binding proteins; binding sites; Biological Sciences; CCAAT-Enhancer-Binding Protein-alpha - physiology; Cell cycle; Cell lines; cell proliferation; cyclin-dependent kinase; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; gene overexpression; Genes; Genetic loci; Genetic mutation; Homeodomain Proteins - physiology; humans; Leukemia; Leukemia, Experimental - physiopathology; loci; Mice; Myeloid Ecotropic Viral Integration Site 1 Protein; Myeloid leukemia; Neoplasm Proteins - physiology; Promoter Regions, Genetic; Protein Binding; Spleen cells; stem cells; Transcription factors; gene regulation; enhancer
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1402238111

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/EBPα) as a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis. We show that C/EBPα is required for the proliferation of Hoxa9/Meis1-transformed cells in culture and that loss of C/EBPα 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/EBPα, 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/EBPα to overcome a block in G1 cell cycle progression. Together, our results suggest a previously unidentified role for C/EBPα in maintaining the proliferation required for Hoxa9/Meis1-mediated leukemogenesis.