Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia
Year: 2019
Type: article
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. 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.
Source: Nature Communications
Authors: 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 Di Genua, Roy Drissen, Claus Nerlov, Soheil Meshinchi, Lucia Carbone, Brian J. Druker, Julia E. Maxson
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: National Science Foundation, Collins Medical Trust, Oregon Health and Science University, European Hematology Association, National Institutes of Health, Oregon National Primate Research Center, Knight Cancer Institute, Oregon Health and Science University, Medical Research Council, National Human Genome Research Institute, National Cancer Institute, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1294778923, G2034128388, G301932103, Genomic Sequencing of Aged Nonhuman Primates at ONPRC, Comparative and functional analysis of conservation and rearrangement of topologically associating domains across mammals., G4267807453, G4271287713, G4444992757, G5108495837, G5992890995, G612088482, G6623253635, G68110818, G767264164, G8343636855, G860380395, Collaborative Research: Impact of a novel retrotransposon expansion on centromere function, G9000003089, G9000046723, G9000172407, G9000184446, G9000219726, Architecture and Trajectory of Acquired Resistance to Therapy in AML, Institutional Career Development Core, G997771125
OpenAlex ID: W2990499535