dataset
posted on 2023-04-03, 21:40 authored by Fiona C. Brown, Eric Still, Richard P. Koche, Christina Y. Yim, Sumiko Takao, Paolo Cifani, Casie Reed, Shehana Gunasekera, Scott B. Ficarro, Peter Romanienko, Willie Mark, Craig McCarthy, Elisa de Stanchina, Mithat Gonen, Venkatraman Seshan, Patrick Bhola, Conor O'Donnell, Barbara Spitzer, Crystal Stutzke, Vincent-Philippe Lavallée, Josée Hébert, Andrei V. Krivtsov, Ari Melnick, Elisabeth M. Paietta, Martin S. Tallman, Anthony Letai, Guy Sauvageau, Gayle Pouliot, Ross Levine, Jarrod A Marto, Scott A. Armstrong, Alex Kentsis Processed data for MRT199665 and DMSO treated OCI-AML2 cells by RNA sequencing
Funding
NIH
Burroughs Wellcome Fund
Rita Allen Foundation
Alex's Lemonade Stand Foundation
American Society of Hematology
Gabrielle's Angel Foundation
Damon Runyon-Richard Lumsden Foundation
History
ARTICLE 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. Cancer Discov; 8(4); 478–97. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371
