TitleMEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia.
Publication TypeJournal Article
Year of Publication2018
AuthorsBrown, Fiona C., Still Eric, Koche Richard P., Yim Christina Y., Takao Sumiko, Cifani Paolo, Reed Casie, Gunasekera Shehana, Ficarro Scott B., Romanienko Peter, Mark Willie, McCarthy Craig, de Stanchina Elisa, Gönen Mithat, Seshan Venkatraman, Bhola Patrick, O'Donnell Conor, Spitzer Barbara, Stutzke Crystal, Lavallée Vincent-Philippe, Hébert Josée, Krivtsov Andrei V., Melnick Ari, Paietta Elisabeth M., Tallman Martin S., Letai Anthony, Sauvageau Guy, Pouliot Gayle, Levine Ross, Marto Jarrod A., Armstrong Scott A., and Kentsis Alex
JournalCancer Discov
Date Published2018 Apr
KeywordsAnimals, Antineoplastic Agents, Cell Line, Drug Resistance, Neoplasm, Gene Expression Regulation, Leukemic, Humans, Leukemia, Myeloid, Acute, MEF2 Transcription Factors, Mice, Mice, Transgenic, Phosphorylation, Protein Processing, Post-Translational, Proteomics

<p>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 knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by 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. 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. .</p>

Alternate JournalCancer Discov
PubMed ID29431698
PubMed Central IDPMC5882571
Grant ListU54 OD020355 / OD / NIH HHS / United States
R01 CA204396 / CA / NCI NIH HHS / United States
U24 CA196172 / CA / NCI NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R21 CA188881 / CA / NCI NIH HHS / United States
K12 CA184746 / CA / NCI NIH HHS / United States