PML-RARA抑制PPARG的活性诱导急性早幼粒白血病脂代谢异常的机制

急性早幼粒白血病（APL）患者在一线治疗过程中常出现脂代谢异常，但其异常机制及初诊病人的脂质状态并不清楚。通过回顾性临床数据分析，我们发现初诊APL患者血清中甘油三酯、胆固醇、低密度脂蛋白和高密度脂蛋白的表达水平与非APL患者相比明显升高。APL移植模型结果显示，受体小鼠随移植时间延长呈现脂代谢异常，表明APL细胞可能介导了机体脂质代谢异常。我们进一步发现APL细胞中代谢相关PPARG信号通路异常，PPARG活性降低，Resistin表达升高，PML-RARA和PPARG存在相互作用并呈负相关。该项目将在分子、细胞及动物水平研究APL病人脂代谢异常的具体机制，为APL代谢异常的治疗提供潜在理论依据及治疗策略。

Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy in clinical research, the underlying molecular mechanism and the lipid status in the patients with newly diagnosed APL remain to be addressed. Here, we report that APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy revealed by a retrospective study. The initial levels of TG、TC、HDL and LDL before treatment were higher in the APL patients than in the non-APL patients. Meanwhile, dyslipidemia was found in Pml-rara transgenic mice (APL mice) and normal mice transplanted with APL cells. These suggested that APL cells mediated Dyslipidemia. Then we found that in APL patients, PPARG signaling was dysregulated, PPARG activity was reduced, the expression of resisitin was elevated and the expression of PML-RARA was negatively correlated with that of PPARG in APL cells. Our work will explore the mechanism of dyslipidemia in APL patients from molecular, cellular and animal levels, which may provide a potential foundation and therapeutic strategy for the APL patients with dyslipidemia.