肥胖通过PPARα促进早幼粒细胞白血病发生的分子机制研究

As a global health problem, obesity is a risk factor for many malignant tumors including leukemia. Recently, the research on the mechanism of how obesity influences leukemia has attracted much attention. Multiple epidemiological studies and our meta-analysis have shown that obesity rates are very significant in patients with acute promyelocytic leukemia (APL) and the prognosis of APL patients with overweight or obese are worse. The results in APL transplantable mouse model also showed that obese mice develop APL earlier. By RNA-seq and differentially expressed genes screening of obese and normal-weight APL samples, we found the effect of obesity on APL occurrence may be resulted from the increase of PPARα and FLT3. In our study, we will explore how PPARα regulates FLT3 and promotes the development of APL during obesity. We will first verify the association between obesity and APL, explore the expression of PPARα and FLT3 in obese APL samples and their functions in cell proliferation, differentiation, apoptosis of APL cells, explain the specific mechanism of PPARα regulating FLT3, and finally explore the potential therapeutic effects of PPARα and FLT3 in mouse model. The study is expected to offer new therapeutic targets for APL and provide new insights into the mechanisms of AML and other solid tumors.

肥胖作为一类全球性的健康问题是包括白血病在内的多种恶性肿瘤的高危因素，近年来其对白血病发生发展的机制研究备受瞩目。多项流行病学及我们的荟萃研究结果均显示，急性早幼粒细胞白血病（APL）患者中的肥胖率非常显著，超重或肥胖的APL患者预后更差。前期我们在APL可移植小鼠模型中也发现肥胖小鼠更容易发生APL，通过RNA-seq等对肥胖及正常体重组APL样本的差异基因进行筛选，发现肥胖促发APL可能与PPARα及FLT3的增高有关。本课题拟探索肥胖情况下，PPARα如何调控FLT3，进而促进APL发生的机制。我们将首先验证肥胖与APL发生的关联，探索PPARα及FLT3的表达情况及其对APL细胞增殖、分化、凋亡功能的影响，发掘PPARα调控FLT3的具体机制，最后在小鼠模型中探索PPARα和FLT3的潜在治疗作用。该研究有望为APL提供新的治疗靶点，并为AML及其他肿瘤的机制研究提供新思路。