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

dc.contributor.authorCollins, Cailin
dc.contributor.authorWang, Jingya
dc.contributor.authorMiao, Hongzhi
dc.contributor.authorBronstein, Joel
dc.contributor.authorNawer, Humaira
dc.contributor.authorXu, Tao
dc.contributor.authorFigueroa, Maria
dc.contributor.authorMuntean, Andrew G.
dc.contributor.authorHess, Jay L.
dc.contributor.departmentDepartment of Medicine, IU School of Medicineen_US
dc.date.accessioned2016-02-26T20:18:26Z
dc.date.available2016-02-26T20:18:26Z
dc.date.issued2014-07-08
dc.description.abstractHomeobox 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.en_US
dc.identifier.citationCollins, C., Wang, J., Miao, H., Bronstein, J., Nawer, H., Xu, T., … Hess, J. L. (2014). C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis. Proceedings of the National Academy of Sciences of the United States of America, 111(27), 9899–9904. http://doi.org/10.1073/pnas.1402238111en_US
dc.identifier.urihttps://hdl.handle.net/1805/8544
dc.language.isoen_USen_US
dc.publisherPNASen_US
dc.relation.isversionof10.1073/pnas.1402238111en_US
dc.relation.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectEnhanceren_US
dc.subjectGene regulationen_US
dc.titleC/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesisen_US
dc.typeArticleen_US
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