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MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia

Fiona C Brown1, Eric Still1, Richard P Koche2

  • 1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.

Cancer Discovery
|February 13, 2018
PubMed

Insights

Chemotherapy resistance in acute myeloid leukemia (AML) is linked to MEF2C phosphorylation. Inhibiting MARK/SIK kinases with MRT199665 shows promise for treating resistant AML by targeting this pathway.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Chemotherapy resistance is a major challenge in treating acute myeloid leukemia (AML).
  • The underlying mechanisms of primary chemoresistance in AML are not fully understood.

Purpose of the Study:

  • To identify molecular markers and therapeutic targets for chemoresistant AML.
  • To investigate the role of MEF2C phosphorylation in AML chemoresistance and leukemogenesis.

Main Methods:

  • Functional proteomics was employed on patient AML specimens.
  • MEF2C phosphorylation status was analyzed in relation to chemoresistance.
  • Mice with engineered MEF2C mutations were used to study leukemogenesis.
  • The effects of MARK/SIK inhibitor MRT199665 were tested on AML cell lines and patient samples.

Main Results:

  • MEF2C S222 phosphorylation was identified as a specific marker of primary chemoresistance in AML.
  • MEF2C phosphorylation is essential for leukemia stem cell maintenance and is induced by MARK kinases.
  • Inhibition of MARK/SIK kinases with MRT199665 induced apoptosis and chemosensitivity in MEF2C-activated AML, but not in others.
  • These findings highlight kinase-dependent transcription factor dysregulation as a determinant of AML therapy response.

Conclusions:

  • MEF2C phosphorylation is a key determinant of therapy response in AML.
  • Targeting MARK/SIK kinases offers a potential therapeutic strategy for chemoresistant AML.
  • This research provides a basis for improved diagnosis and treatment of AML.

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