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. Smith, 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. RiesShannon McWeeney, Cristina Di Genua, Roy Drissen, Claus Nerlov, Soheil Meshinchi, Lucia Carbone, Brian J. Druker, Julia E. Maxson

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Article number5455
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Braun, T. P., Okhovat, M., Coblentz, C., Carratt, S. A., Foley, A., Schonrock, Z., Smith, B. M., Nevonen, K., Davis, B., Garcia, B., LaTocha, D., Weeder, B. R., Grzadkowski, M. R., Estabrook, J. C., Manning, H. G., Watanabe-Smith, K., Jeng, S., Smith, J. L., Leonti, A. R., ... Maxson, J. E. (2019). Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia. Nature communications, 10(1), [5455]. https://doi.org/10.1038/s41467-019-13364-2