MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia

Cancer Discov. 2018 Apr;8(4):478-497. doi: 10.1158/2159-8290.CD-17-1271.

Fiona C Brown ¹, Eric Still ¹, Richard P Koche ², Christina Y Yim ¹, Sumiko Takao ¹, Paolo Cifani ¹, Casie Reed ¹, Shehana Gunasekera ¹, Scott B Ficarro ³, Peter Romanienko ⁴, Willie Mark ⁴, Craig McCarthy ¹, Elisa de Stanchina ¹, Mithat Gonen ⁵, Venkatraman Seshan ⁵, Patrick Bhola ⁶, Conor O'Donnell ¹, Barbara Spitzer ⁷, Crystal Stutzke ⁸, Vincent-Philippe Lavallée ⁹ ¹⁰, Josée Hébert ⁹ ¹⁰ ¹¹ ¹², Andrei V Krivtsov ² ¹³, Ari Melnick ¹⁴, Elisabeth M Paietta ¹⁵, Martin S Tallman ¹⁶, Anthony Letai ⁶ ¹⁷, Guy Sauvageau ⁹ ¹⁰ ¹¹ ¹², Gayle Pouliot ⁶, Ross Levine ² ⁷ ¹⁶ ¹⁸, Jarrod A Marto ³, Scott A Armstrong ² ¹³, Alex Kentsis ¹⁹ ⁷ ¹⁴

Affiliations

1 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
2 Center for Epigenetics Research, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
4 Mouse Genetics Core Facility, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
5 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
7 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
8 PhosphoSolutions, Aurora, Colorado.
9 The Leucegene Project at Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
10 Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
11 Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
12 Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
13 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
14 Departments of Pediatrics, Pharmacology, and Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, New York.
15 Montefiore Medical Center-North Division, Albert Einstein College of Medicine, Bronx, New York, New York.
16 Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York.
17 Harvard Medical School, Boston, Massachusetts.
18 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, New York.
19 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York. [email protected].

PMID: 29431698 DOI: 10.1158/2159-8290.CD-17-1271

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 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. Cancer Discov; 8(4); 478-97. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-120877

MRT199665

99.92%, MARK/SIK/AMPK Inhibitor

Salt-inducible Kinase (SIK); AMPK; Apoptosis

Cancer

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