Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature communications, 2019-11, Vol.10 (1), p.5455-15, Article 5455

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Acute Myeloid Leukemia (AML) develops following multiple mutations of differing impact. Here, the authors show that activating mutations of CSF3R co-operate with loss-of-function mutations of CEBPA to promote AML development through an enhancer-dependent mechanism.