MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia. Academic Article uri icon

Overview

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.

authors

publication date

  • February 5, 2018

Research

keywords

  • Antineoplastic Agents
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Leukemic
  • Leukemia, Myeloid, Acute
  • MEF2 Transcription Factors
  • Protein Processing, Post-Translational

Identity

PubMed Central ID

  • PMC5882571

Scopus Document Identifier

  • 85047852099

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-17-1271

PubMed ID

  • 29431698

Additional Document Info

volume

  • 8

issue

  • 4