MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia,Cancer Discovery

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MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia
Cancer Discovery ( IF 29.7 ) Pub Date : 2018-04-01 , DOI: 10.1158/2159-8290.cd-17-1271
Fiona C Brown ₁ , Eric Still ₁ , Richard P Koche ₂ , Christina Y Yim ₁ , Sumiko Takao ₁ , Paolo Cifani ₁ , Casie Reed ₁ , Shehana Gunasekera ₁ , Scott B Ficarro ₃ , Peter Romanienko ₄ , Willie Mark ₄ , Craig McCarthy ₁ , Elisa de Stanchina ₁ , Mithat Gonen ₅ , Venkatraman Seshan ₅ , Patrick Bhola ₆ , Conor O'Donnell ₁ , Barbara Spitzer ₇ , Crystal Stutzke ₈ , Vincent-Philippe Lavallée _{9,

10} , Josée Hébert _{9,

10,

11,

12} , Andrei V Krivtsov _{2,

13} , Ari Melnick ₁₄ , Elisabeth M Paietta ₁₅ , Martin S Tallman ₁₆ , Anthony Letai _{6,

17} , Guy Sauvageau _{9,

10,

11,

12} , Gayle Pouliot ₆ , Ross Levine _{2,

7,

16,

18} , Jarrod A Marto ₃ , Scott A Armstrong _{2,

13} , Alex Kentsis _{1,

7,

14}

Affiliation

Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
Center for Epigenetics Research, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
Mouse Genetics Core Facility, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
PhosphoSolutions, Aurora, Colorado.
The Leucegene Project at Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Departments of Pediatrics, Pharmacology, and Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, New York.
Montefiore Medical Center-North Division, Albert Einstein College of Medicine, Bronx, New York, New York.
Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Harvard Medical School, Boston, Massachusetts.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, New York.

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/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/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. Cancer Discov; 8(4); 478–97. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 371

中文翻译：

急性髓系白血病化疗耐药需要 MEF2C 磷酸化

在急性髓系白血病 (AML) 中，化疗耐药仍然普遍存在，但人们对此知之甚少。利用患者 AML 样本的功能蛋白质组学，我们确定 MEF2C S222 磷酸化是原发性化疗耐药的特异性标志物。我们发现，经过工程改造以阻断 MEF2C 磷酸化的 Mef2c ^S222A/S222A敲入突变小鼠表现出正常的造血功能，但对MLL-AF9诱导的白血病发生具有抵抗力。 MEF2C 磷酸化是白血病干细胞维持所必需的，并由细胞中的 MARK 激酶诱导。使用选择性 MARK/SIK 抑制剂 MRT199665 进行治疗会导致 MEF2C 激活的人 AML 细胞系和原发性患者标本发生细胞凋亡并赋予化疗敏感性，但对于缺乏 MEF2C 磷酸化的细胞则不会。这些发现确定激酶依赖性转录因子控制失调是 AML 治疗反应的决定因素，具有改善该疾病诊断和治疗的直接潜力。

这篇文章在本期特稿中重点介绍，第 17 页。第371章

更新日期：2018-04-02

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