Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia

Theodore P. Braun, Mariam Okhovat, Cody Coblentz, Sarah A. Carratt, Amy Foley, Zachary Schonrock, Brittany M. Curtiss, Kimberly Nevonen, Brett Davis, Brianna Garcia, Dorian LaTocha, Benjamin R. Weeder, Michal R. Grzadkowski, Joey C. Estabrook, Hannah G. Manning, Kevin Watanabe-Smith, Sophia Jeng, Jenny L. Smith, Amanda R. Leonti, Rhonda E. Ries, Shannon McWeeney, Cristina Genua, Roy Drissen, Claus Nerlov, Soheil Meshinchi, Lucia Carbone, Brian J. Druker and Julia E. Maxson ()
Additional contact information
Theodore P. Braun: Oregon Health & Science University
Mariam Okhovat: Oregon Health & Science University
Cody Coblentz: Oregon Health & Science University
Sarah A. Carratt: Oregon Health & Science University
Amy Foley: Oregon Health & Science University
Zachary Schonrock: Oregon Health & Science University
Brittany M. Curtiss: Oregon Health & Science University
Kimberly Nevonen: Oregon Health & Science University
Brett Davis: Oregon Health & Science University
Brianna Garcia: Oregon Health & Science University
Dorian LaTocha: Oregon Health & Science University
Benjamin R. Weeder: Oregon Health & Science University
Michal R. Grzadkowski: Oregon Health & Science University
Joey C. Estabrook: Oregon Health & Science University
Hannah G. Manning: Oregon Health & Science University
Kevin Watanabe-Smith: Oregon Health & Science University
Sophia Jeng: Oregon Health & Science University
Jenny L. Smith: Fred Hutchinson Cancer Research Center
Amanda R. Leonti: Fred Hutchinson Cancer Research Center
Rhonda E. Ries: Fred Hutchinson Cancer Research Center
Shannon McWeeney: Oregon Health & Science University
Cristina Genua: John Radcliffe Hospital
Roy Drissen: John Radcliffe Hospital
Claus Nerlov: John Radcliffe Hospital
Soheil Meshinchi: Fred Hutchinson Cancer Research Center
Lucia Carbone: Oregon Health & Science University
Brian J. Druker: Oregon Health & Science University
Julia E. Maxson: Oregon Health & Science University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a 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. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.

Date: 2019
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DOI: 10.1038/s41467-019-13364-2

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