MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

Fiona C. Brown, Eric Still, Richard P. Koche, Christina Y. Yim, Sumiko Takao, Paolo Cifani, Casie Reed, Shehana Gunasekera, Scott B. Ficarro, Peter Romanienko, Willie Mark, Craig McCarthy, Elisa de Stanchina, Mithat Gonen, Venkatraman Seshan, Patrick Bhola, Conor O’Donnell, Barbara Spitzer, Crystal Stutzke, Vincent Philippe Lavallée & 12 others Josée Hébert, Andrei V. Krivtsov, Ari Melnick, Elisabeth M. Paietta, Martin S. Tallman, Anthony Letai, Guy Sauvageau, Gayle Pouliot, Ross Levine, Jarrod A. Marto, Scott A. Armstrong, Alex Kentsis

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)478-497
Number of pages20
JournalCancer Discovery
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2018

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Acute Myeloid Leukemia
Phosphorylation
Drug Therapy
Phosphotransferases
ditazol
Proteomics
Transcription Factors
Hematopoiesis
Myeloid Cells
Therapeutics
Leukemia
Stem Cells
Maintenance
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Oncology

Cite this

Brown, F. C., Still, E., Koche, R. P., Yim, C. Y., Takao, S., Cifani, P., ... Kentsis, A. (2018). MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia. Cancer Discovery, 8(4), 478-497. https://doi.org/10.1158/2159-8290.CD-17-1271

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia. / Brown, 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; Gonen, 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.; Kentsis, Alex.

In: Cancer Discovery, Vol. 8, No. 4, 01.04.2018, p. 478-497.

Research output: Contribution to journalArticle

Brown, FC, Still, E, Koche, RP, Yim, CY, Takao, S, Cifani, P, Reed, C, Gunasekera, S, Ficarro, SB, Romanienko, P, Mark, W, McCarthy, C, de Stanchina, E, Gonen, M, Seshan, V, Bhola, P, O’Donnell, C, Spitzer, B, Stutzke, C, Lavallée, VP, Hébert, J, Krivtsov, AV, Melnick, A, Paietta, EM, Tallman, MS, Letai, A, Sauvageau, G, Pouliot, G, Levine, R, Marto, JA, Armstrong, SA & Kentsis, A 2018, 'MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia', Cancer Discovery, vol. 8, no. 4, pp. 478-497. https://doi.org/10.1158/2159-8290.CD-17-1271
Brown, 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 ; Gonen, 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. ; Kentsis, Alex. / MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia. In: Cancer Discovery. 2018 ; Vol. 8, No. 4. pp. 478-497.
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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.",
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AU - Brown, Fiona C.

AU - Still, Eric

AU - Koche, Richard P.

AU - Yim, Christina Y.

AU - Takao, Sumiko

AU - Cifani, Paolo

AU - Reed, Casie

AU - Gunasekera, Shehana

AU - Ficarro, Scott B.

AU - Romanienko, Peter

AU - Mark, Willie

AU - McCarthy, Craig

AU - de Stanchina, Elisa

AU - Gonen, Mithat

AU - Seshan, Venkatraman

AU - Bhola, Patrick

AU - O’Donnell, Conor

AU - Spitzer, Barbara

AU - Stutzke, Crystal

AU - Lavallée, Vincent Philippe

AU - Hébert, Josée

AU - Krivtsov, Andrei V.

AU - Melnick, Ari

AU - Paietta, Elisabeth M.

AU - Tallman, Martin S.

AU - Letai, Anthony

AU - Sauvageau, Guy

AU - Pouliot, Gayle

AU - Levine, Ross

AU - Marto, Jarrod A.

AU - Armstrong, Scott A.

AU - Kentsis, Alex

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

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