1. Myeloid Lineage Enhancers Drive Oncogene Synergy in CEBPA/CSF3R Mutant Acute Myeloid Leukemia
- Author
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Hannah G. Manning, Mariam Okhovat, Soheil Meshinchi, Brianna Garcia, Joey C. Estabrook, Kevin Watanabe-Smith, Cristina Di Genua, Theodore P. Braun, Shannon K. McWeeney, Brian J. Druker, Rhonda E. Ries, Sophia Jeng, Kimberly A. Nevonen, Claus Nerlov, Roy Drissen, Brett Davis, Dorian LaTocha, Julia E. Maxson, Zachary Schonrock, Lucia Carbone, Amanda R. Leonti, Amy Foley, Benjamin R. Weeder, Sarah A. Carratt, Cody Coblentz, Jenny L. Smith, and Michal R. Grzadkowski
- Subjects
0303 health sciences ,Acute leukemia ,Myeloid ,Lineage (genetic) ,Myeloid leukemia ,Biology ,Core binding factor ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,CEBPA ,Cancer research ,medicine ,Granulocyte colony-stimulating factor receptor ,Transcription factor ,030304 developmental biology - Abstract
Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. This finding of mutation-synergy is broadly applicable other mutations that activate the JAK/STAT pathway or disrupt CEBPA function (i.e. activating mutations in JAK3 and Core Binding Factor translocations). The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation, confirming predictions from clinical sequencing data. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.
- Published
- 2019
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