PRMT1甲基化DUSP4降低急性髓系白血病对阿糖胞苷敏感性的机制研究

急性髓系白血病（AML）生物学特性复杂，整体预后差。蒽环类联合阿糖胞苷(Ara-C)治疗仍是AML治疗的主要治疗方案。巩固治疗时，因患者对大剂量Ara-C耐受性差限制其足量应用。因此我们致力于寻求阿糖胞苷的协同药物以达到最佳治疗效果。我们前期发现：蛋白精氨酸甲基化转移酶1（PRMT1）能缩短具有AML融合基因小鼠发生AML的潜伏期;PRMT1甲基化双特异性磷酸酶（DUSP4）导致其泛素化降解;DUSP4的表达量与AML对Ara-C的敏感性呈正相关;但是其中的具体机制不详。PRMT1抑制剂是否通过抑制DUSP4的降解来提高AML对Ara-C的敏感性及其中的机制仍需进一步研究。本研究拟从分子，细胞和小鼠模型等多方面通过体内体外来研究上述现象及其详细机制，明确PRMT1在通路中的核心作用及PRMT1抑制剂与Ara-C在治疗AML时具有协同作用,将为AML的联合治疗提供理论基础。

Acute myeloid leukemia (AML) has complex biological characteristics with poor prognosis. Anthracycline combined with Ara-C is still the main treatment for AML. During the consolidating period of the treatment, the patient's poor tolerance to high doses of Ara-C limits its adequate application. Therefore, we are committed to seek the synergistic drugs of cytarabine to achieve the best therapeutic effect. our preliminary data revealed that Protein Arginine Methyltransferase1 ( PRMT1 ) can shorten the latent period of AML in mice with AML fusion gene. Dual specific phosphatase 4 (DUSP4) is a methylation target of PRMT1 and DUSP4 protein stability is decreased upon PRMT1 mediated methylation. Furthermore, the expression of DUSP4 is positively correlated with the sensitivity of AML to Ara-C, but the detailed mechanism remains unknown.whether PRMT1 inhibitors increase the sensitivity of AML to Ara-C by inhibiting the degradation of DUSP4 and the mechanisms involved in need to be further study . In this study, we will clarify this phenomenon in vivo/vitro from mouse models, molecular and cells to reveal the core role of PRMT1 in the pathway and the synergistic effect of PRMT1 inhibitor and Ara-C in the treatment of AML.This study will provide theoretical basis for the combined treatment of AML.