RT Journal Article
SR Electronic
T1 MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 107201
DO 10.1101/107201
A1 Fiona C. Brown
A1 Eric Still
A1 Paolo Cifani
A1 Sumiko Takao
A1 Casie Reed
A1 Scott B. Ficarro
A1 Richard P. Koche
A1 Peter Romanienko
A1 Willie Mark
A1 Conor O’Donnell
A1 Barbara Spitzer
A1 Crystal Stutzke
A1 Andrei V. Krivtsov
A1 Gayle Pouliot
A1 Nathanael Gray
A1 Jarrod A. Marto
A1 Scott Armstrong
A1 Alex Kentsis
YR 2017
UL http://biorxiv.org/content/early/2017/02/09/107201.abstract
AB HIGHLIGHTSMEF2C S222 phosphorylation is a specific marker of chemotherapy resistance in diagnostic AML patient specimens.MEF2C S222 phosphorylation is dispensable for normal hematopoiesis in mice, as established using genome editing in vivo, but is required for MLL-AF9 induced leukemogenesis.MARK kinases specifically phosphorylate MEF2C S222, potentiating its transcriptional activity.Chemical inhibition of MARK-induced MEF2C phosphorylation overcomes chemotherapy resistance of and exhibits selectivity toxicity against MEF2C-activated human AML cells.SUMMARY In 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.