期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 27, 页码 9899-9904出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1402238111
关键词
enhancer; gene regulation
资金
- National Institutes of Health [R01 CA151425-01, F30 CA171917-01A1]
- Leukemia and Lymphoma Society
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 cofactormeis 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 alpha) as a critical collaborator required for Hoxa9/Meis1-mediated leukemogenesis. We show that C/EBP alpha is required for the proliferation of Hoxa9/Meis1-transformed cells in culture and that loss of C/EBP alpha 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 alpha, 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 alpha to overcome a block in G1 cell cycle progression. Together, our results suggest a previously unidentified role for C/EBP alpha in maintaining the proliferation required for Hoxa9/Meis1-mediated leukemogenesis.
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