MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia

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, Lavallée, Vincent-Philippe, Hébert, Josée, Krivtsov, Andrei V, Melnick, Ari, Paietta, Elisabeth M, Tallman, Martin S, Letai, Anthony, Sauvageau, Guy, Pouliot, Gayle, Levine, Ross, Marto, Jarrod A, Armstrong, Scott A, Kentsis, Alex (April 2018) MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia. Cancer Discovery, 8 (4). pp. 478-497. ISSN 2159-8274

Abstract

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 Mef2cS222A/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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification diseases & disorders > cancer > cancer types > acute myeloid leukemia organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > drugs and therapies > chemoresistance diseases & disorders > cancer > cancer types > leukemia organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > phosphorylation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor diseases & disorders > cancer > cancer types
CSHL Authors:	Cifani, Paolo
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	1 April 2018
Date Deposited:	01 Feb 2023 17:18
Last Modified:	07 Feb 2024 18:31
PMCID:	PMC5882571
URI:	https://repository.cshl.edu/id/eprint/40823

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