MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia [mutant MEF2C]

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 transgenic Mef2cS222A/S222A 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, induced by MARK kinases in cells, and blocked by selective MARK inhibitor MRT199665, which caused apoptosis of MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C. These findings identify signaling-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. Overall design: RNA-sequencing of human leukemia cell line with induction of wildtype or mutant MEF2C.急性髓系白血病（acute myeloid leukemia, AML）中，化疗耐药仍普遍存在且机制尚未阐明。本研究针对患者AML标本开展功能蛋白质组学分析，鉴定出MEF2C S222磷酸化可作为原发性化疗耐药的特异性标志物。本研究构建了阻断MEF2C磷酸化的转基因Mef2cS222A/S222A小鼠，该小鼠造血功能正常，但可抵抗MLL-AF9诱导的白血病发生。研究发现，细胞内MARK激酶可诱导MEF2C磷酸化，而该磷酸化过程是维持白血病干细胞干性所必需的；选择性MARK抑制剂MRT199665可阻断这一磷酸化过程，进而诱导MEF2C激活的人AML细胞系及患者原发白血病标本发生凋亡，但对缺乏MEF2C的样本无此效应。上述研究结果表明，信号依赖的转录因子调控异常是AML患者治疗反应的关键决定因素，该发现可为该疾病的诊断与治疗优化提供直接的临床应用潜力。总体实验设计：对诱导表达野生型或突变型MEF2C的人白血病细胞系进行RNA测序（RNA-sequencing）。