MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Janus Kinase 2
  • Myeloproliferative Disorders
  • Protein Kinase Inhibitors

abstract

  • ©2018 American Association for Cancer Research. 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.

authors

publication date

  • April 2018

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5882571

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-17-1271

PubMed ID

  • 29431698

Additional Document Info

start page

  • 478

end page

  • 497

volume

  • 8

number

  • 4