MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

Brown, F.; Still, E.; Cifani, P.; Takao, S.; Reed, C.; Ficarro, S.; Koche, R.; Romanienko, P.; Mark, W.; O'Donnell, C.; Spitzer, B.; Stutzke, C.; Krivtsov, A.; Pouliot, G.; Marto, J.; Armstrong, S.; Kentsis, A.

doi:10.1101/107201

bioRxiv · 10.1101/107201

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

Brown, F.·Still, E.·Cifani, P.·Takao, S.·Reed, C.·Ficarro, S.·Koche, R.·Romanienko, P.·Mark, W.·O'Donnell, C.·Spitzer, B.·Stutzke, C.·Krivtsov, A.·Pouliot, G.·Marto, J.·Armstrong, S.·Kentsis, A.

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Abstract

HIGHLIGHTSO_LIMEF2C S222 phosphorylation is a specific marker of chemotherapy resistance in diagnostic AML patient specimens.\nC_LIO_LIMEF2C S222 phosphorylation is dispensable for normal hematopoiesis in mice, as established using genome editing in vivo, but is required for MLL-AF9 induced leukemogenesis.\nC_LIO_LIMARK kinases specifically phosphorylate MEF2C S222, potentiating its transcriptional activity.\nC_LIO_LIChemical inhibition of MARK-induced MEF2C phosphorylation overcomes chemotherapy resistance of and exhibits selectivity toxicity against MEF2C-activated human AML cells.\nC_LI\n\nSUMMARYIn acute myeloid leukemia, 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 inhibitor MRT199665 caused apoptosis of 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.

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Brown, F., Still, E., Cifani, P., Takao, S., Reed, C., Ficarro, S., Koche, R., Romanienko, P., Mark, W., O'Donnell, C., Spitzer, B., Stutzke, C., Krivtsov, A., Pouliot, G., Marto, J., Armstrong, S., Kentsis, A.. 2017-02-09. MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia. https://doi.org/10.1101/107201

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