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; 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

doi:10.1158/2159-8290.CD-17-1271

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 LavalléeJosée 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

Oncology

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

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 Mef2c^S222A/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 language	English (US)
Pages (from-to)	478-497
Number of pages	20
Journal	Cancer discovery
Volume	8
Issue number	4
DOIs	https://doi.org/10.1158/2159-8290.CD-17-1271
State	Published - Apr 2018

ASJC Scopus subject areas

Oncology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-17-1271

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Brown, F. C., Still, E., Koche, R. P., Yim, C. Y., Takao, S., Cifani, P., Reed, C., Gunasekera, S., Ficarro, S. B., Romanienko, P., Mark, W., McCarthy, C., de Stanchina, E., Gonen, M., Seshan, V., Bhola, P., O’Donnell, C., Spitzer, B., Stutzke, C., ... 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

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

@article{64954849cf924c6ba250d9b342df50e6,

title = "MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia",

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.",

author = "Brown, {Fiona C.} and Eric Still and Koche, {Richard P.} and Yim, {Christina Y.} and Sumiko Takao and Paolo Cifani and Casie Reed and Shehana Gunasekera and Ficarro, {Scott B.} and Peter Romanienko and Willie Mark and Craig McCarthy and {de Stanchina}, Elisa and Mithat Gonen and Venkatraman Seshan and Patrick Bhola and Conor O{\textquoteright}Donnell and Barbara Spitzer and Crystal Stutzke and Lavall{\'e}e, {Vincent Philippe} and Jos{\'e}e H{\'e}bert and Krivtsov, {Andrei V.} and Ari Melnick and Paietta, {Elisabeth M.} and Tallman, {Martin S.} and Anthony Letai and Guy Sauvageau and Gayle Pouliot and Ross Levine and Marto, {Jarrod A.} and Armstrong, {Scott A.} and Alex Kentsis",

note = "Publisher Copyright: {\textcopyright}2018 American Association for Cancer Research.",

year = "2018",

month = apr,

doi = "10.1158/2159-8290.CD-17-1271",

language = "English (US)",

volume = "8",

pages = "478--497",

journal = "Cancer discovery",

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publisher = "American Association for Cancer Research Inc.",

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T1 - MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

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

Y1 - 2018/4

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.

AB - 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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U2 - 10.1158/2159-8290.CD-17-1271

DO - 10.1158/2159-8290.CD-17-1271

M3 - Article

C2 - 29431698

AN - SCOPUS:85047852099

SN - 2159-8274

VL - 8

SP - 478

EP - 497

JO - Cancer discovery

JF - Cancer discovery

IS - 4

ER -

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

Abstract

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