title: C/EBPα 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/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.
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.
authors: Cailin
authors: C
authors: Collins
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.
authors: Jingya
authors: J
authors: Wang
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.
authors: Hongzhi
authors: H
authors: Miao
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.
authors: Joel
authors: J
authors: Bronstein
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.
authors: Humaira
authors: H
authors: Nawer
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.
authors: Tao
authors: T
authors: Xu
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.
authors: Maria
authors: M
authors: Figueroa
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.
authors: Andrew G
authors: AG
authors: Muntean
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; andIndiana University School of Medicine, Indianapolis, IN 46202 jayhess@iu.edu.
authors: Jay L
authors: JL
authors: Hess
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D018398:Homeodomain Proteins / Q000502:physiology*; D007942:Leukemia, Experimental / Q000503:physiopathology*; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C417743:Cdkn2a protein, mouse; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C097899:homeobox protein HOXA9
keywords: enhancer; gene regulation