MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia Journal Article


Authors: Brown, F. C.; Still, E.; Koche, R. P.; Yim, C. Y.; Takao, S.; Cifani, P.; Reed, C.; Gunasekera, S.; Ficarro, S. B.; Romanienko, P.; Mark, W.; McCarthy, C.; de Stanchina, E.; Gonen, M.; Seshan, V.; Bhola, P.; O’Donnell, C.; Spitzer, B.; Stutzke, C.; Lavallée, V. P.; Hébert, J.; Krivtsov, A. V.; Melnick, A.; Paietta, E. M.; Tallman, M. S.; Letai, A.; Sauvageau, G.; Pouliot, G.; Levine, R.; Marto, J. A.; Armstrong, S. A.; Kentsis, A.
Article Title: MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia
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/S222Aknock-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. ©2018 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 8
Issue: 4
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2018-04-01
Start Page: 478
End Page: 497
Language: English
DOI: 10.1158/2159-8290.cd-17-1271
PROVIDER: scopus
PMCID: PMC5882571
PUBMED: 29431698
DOI/URL:
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
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MSK Authors
  1. Venkatraman Ennapadam Seshan
    310 Seshan
  2. Mithat Gonen
    775 Gonen
  3. Martin Stuart Tallman
    492 Tallman
  4. Ross Levine
    539 Levine
  5. Willie Mark
    19 Mark
  6. Barbara Spitzer
    35 Spitzer
  7. Scott Allen Armstrong
    108 Armstrong
  8. Richard Patrick Koche
    63 Koche
  9. Alex   Kentsis
    66 Kentsis
  10. Paolo   Cifani
    23 Cifani
  11. Casie Leigh Reed
    6 Reed
  12. Eric Ryan Still
    9 Still
  13. Fiona Claire Brown
    8 Brown
  14. Christina Yeaeun Yim
    1 Yim
  15. Sumiko Takao
    2 Takao