MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia

作者：Brown Fiona C; Still Eric; Koche Richard P; Yim Christina Y; Takao Sumiko; Cifani Paolo; Reed Casie; Gunasekera Shehana; Ficarro Scott B; Romanienko Peter; Mark Willie; McCarthy Craig; de Stanchina Elisa; Gonen Mithat; Seshan Venkatraman; Bhola Patrick; O'donnell Conor; Spitzer Barbara; Stutzke Crystal; Lavallee Vincent Philippe; Hebert Josee; Krivtsov Andrei V; Melnick Ari; Paietta Elisabeth M; Tallman Martin S; Letai Anthony; Sauvageau Guy; Pouliot Gayle

来源：Cancer Discovery, 2018, 8(4): 478-497.

DOI：10.1158/2159-8290.CD-17-1271

In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2c(S222A/S222A) knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.
SIGNIFICANCE: Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML.

• 出版日期2018-4