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

被引：28

作者：

Braun, Theodore P. ^{[1
,2
]}

Okhovat, Mariam ^{[3
]}

Coblentz, Cody ^{[1
,2
]}

Carratt, Sarah A. ^{[1
,2
]}

Foley, Amy ^{[1
,2
]}

Schonrock, Zachary ^{[1
,2
]}

Smith, Brittany M. ^{[1
,2
]}

Nevonen, Kimberly ^{[3
]}

Davis, Brett ^{[3
]}

Garcia, Brianna ^{[1
,2
]}

LaTocha, Dorian ^{[1
,2
]}

Weeder, Benjamin R. ^{[4
]}

Grzadkowski, Michal R. ^{[5
]}

Estabrook, Joey C. ^{[5
]}

Manning, Hannah G. ^{[5
]}

Watanabe-Smith, Kevin ^{[1
,5
]}

Jeng, Sophia ^{[6
]}

Smith, Jenny L. ^{[7
]}

Leonti, Amanda R. ^{[7
]}

Ries, Rhonda E. ^{[7
]}

McWeeney, Shannon ^{[1
,6
]}

Di Genua, Cristina ^{[8
]}

Drissen, Roy ^{[8
]}

Nerlov, Claus ^{[8
]}

Meshinchi, Soheil ^{[7
,9
]}

Carbone, Lucia ^{[3
,6
,10
]}

Druker, Brian J. ^{[1
,2
,11
]}

Maxson, Julia E. ^{[1
,2
]}

机构：

[1] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA

[2] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR 97239 USA

[3] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97239 USA

[4] Oregon Hlth & Sci Univ, Program Mol & Cellular Biol, Portland, OR 97239 USA

[5] Oregon Hlth & Sci Univ, Computat Biol Program, Portland, OR 97239 USA

[6] Oregon Hlth & Sci Univ, Div Bioinformat & Computat Biol, Portland, OR 97239 USA

[7] Fred Hutchinson Canc Res Ctr, Clin Res Div, 1100 Fairview Ave N, Seattle, WA 98109 USA

[8] John Radcliffe Hosp, MRC Weatherall Inst Mol Med, MRC Mol Haematol Unit, Headley Way, Oxford OX3 9DS, England

[9] Univ Washington, Div Pediat Hematol Oncol, Seattle, WA 98195 USA

[10] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA

[11] Howard Hughes Med Inst, Portland, OR USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家科学基金会;

关键词：

C/EBP-ALPHA; CSF3R MUTATIONS; TRANSCRIPTION; EXPRESSION; REVEALS; DIFFERENTIATION; ACTIVATION; INITIATION; DISCOVERY; CANCER;

D O I：

10.1038/s41467-019-13364-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

共 52 条

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[Anonymous], F1000 RES, DOI DOI 10.12688/F1000RESEARCH.7563.2

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