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. Ries; Shannon McWeeney; Cristina Di Genua; Roy Drissen; Claus Nerlov; Soheil Meshinchi; Lucia Carbone; Brian J. Druker; Julia E. Maxson

doi:10.1038/s41467-019-13364-2

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

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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 language	English (US)
Article number	5455
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13364-2
State	Published - Dec 1 2019

ASJC Scopus subject areas

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

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10.1038/s41467-019-13364-2

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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

Braun, TP, Okhovat, M, Coblentz, C, Carratt, SA, Foley, A, Schonrock, Z, Smith, BM, Nevonen, K, Davis, B, Garcia, B, LaTocha, D, Weeder, BR, Grzadkowski, MR, Estabrook, JC, Manning, HG, Watanabe-Smith, K, Jeng, S, Smith, JL, Leonti, AR, Ries, RE, McWeeney, S, Di Genua, C, Drissen, R, Nerlov, C, Meshinchi, S, Carbone, L , Druker, BJ & Maxson, JE 2019, 'Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia', Nature communications, vol. 10, no. 1, 5455. https://doi.org/10.1038/s41467-019-13364-2

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title = "Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia",

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.",

author = "Braun, {Theodore P.} and Mariam Okhovat and Cody Coblentz and Carratt, {Sarah A.} and Amy Foley and Zachary Schonrock and Smith, {Brittany M.} and Kimberly Nevonen and Brett Davis and Brianna Garcia and Dorian LaTocha and Weeder, {Benjamin R.} and Grzadkowski, {Michal R.} and Estabrook, {Joey C.} and Manning, {Hannah G.} and Kevin Watanabe-Smith and Sophia Jeng and Smith, {Jenny L.} and Leonti, {Amanda R.} and Ries, {Rhonda E.} and Shannon McWeeney and {Di Genua}, Cristina and Roy Drissen and Claus Nerlov and Soheil Meshinchi and Lucia Carbone and Druker, {Brian J.} and Maxson, {Julia E.}",

note = "Funding Information: We are grateful to the following core facilities: Histopathology Shared Resource, Massively Parallel Sequencing Shared Resource, Gene Profiling Shared Resource, Epigenetics Consortium, Knight Cancer Institute Biostatistics Shared Resource, Flow Cytometry Shared Resource, ExaCloud Cluster Computational Resource and the Advanced Computing Center. Funding provided by an American Society of Hematology Research Training Award for Fellows and Collins Medical Trust Award to T.P.B., OHSU School of Medicine Faculty Innovation Fund to B.J.D. and J.E.M., Howard Hughes Medical Institute to B.J.D, NCI R00-CA190605, an ASH Scholar Award, and an MRF New Investigator Grant to J.E.M. NCI U10 CA 98543-08S6, a St. Baldrick{\textquoteright}s Foundation Grant and Help the Hutch Funding to S.M., L.C. and M.O are supported by the National Science Foundation (grant #1613856) and from the National Institute of Health (R01HG010333), L.C. is also supported in part by NIH/OD P51 OD011092 to the Oregon National Primate Research Center. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-019-13364-2",

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T1 - Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia

AU - Braun, Theodore P.

AU - Okhovat, Mariam

AU - Coblentz, Cody

AU - Carratt, Sarah A.

AU - Foley, Amy

AU - Schonrock, Zachary

AU - Smith, Brittany M.

AU - Nevonen, Kimberly

AU - Davis, Brett

AU - Garcia, Brianna

AU - LaTocha, Dorian

AU - Weeder, Benjamin R.

AU - Grzadkowski, Michal R.

AU - Estabrook, Joey C.

AU - Manning, Hannah G.

AU - Watanabe-Smith, Kevin

AU - Jeng, Sophia

AU - Smith, Jenny L.

AU - Leonti, Amanda R.

AU - Ries, Rhonda E.

AU - McWeeney, Shannon

AU - Di Genua, Cristina

AU - Drissen, Roy

AU - Nerlov, Claus

AU - Meshinchi, Soheil

AU - Carbone, Lucia

AU - Druker, Brian J.

AU - Maxson, Julia E.

N1 - Funding Information: We are grateful to the following core facilities: Histopathology Shared Resource, Massively Parallel Sequencing Shared Resource, Gene Profiling Shared Resource, Epigenetics Consortium, Knight Cancer Institute Biostatistics Shared Resource, Flow Cytometry Shared Resource, ExaCloud Cluster Computational Resource and the Advanced Computing Center. Funding provided by an American Society of Hematology Research Training Award for Fellows and Collins Medical Trust Award to T.P.B., OHSU School of Medicine Faculty Innovation Fund to B.J.D. and J.E.M., Howard Hughes Medical Institute to B.J.D, NCI R00-CA190605, an ASH Scholar Award, and an MRF New Investigator Grant to J.E.M. NCI U10 CA 98543-08S6, a St. Baldrick’s Foundation Grant and Help the Hutch Funding to S.M., L.C. and M.O are supported by the National Science Foundation (grant #1613856) and from the National Institute of Health (R01HG010333), L.C. is also supported in part by NIH/OD P51 OD011092 to the Oregon National Primate Research Center. Publisher Copyright: © 2019, The Author(s).

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N2 - 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.

AB - 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.

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JF - Nature Communications

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ER -

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

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