GDF15介导的骨髓脂肪细胞分化异常对急性髓系白血病干细胞增殖能力的影响及机制研究

Bone marrow niche is essential to the oncogenic function of leukemic stem cells (LSCs). As major components of the niche, bone marrow adipocytes are significantly decreased in acute myeloid leukemia (AML). Whether or how this change play a pathological role in AML is poorly understood. We analyzed the histological characteristics and in vitro functions of bone marrow adipocytes in AML. We discovered that BM adipocytes were abnormally differentiated which was mediated by GDF15. Thus, we speculated that the abnormal differentiation of BM adipocytes may play a key role in the maintenance of unlimited proliferation of LSC. We propose to verify this phenomenon by using an extra-medullary GDF15-overexpressing mouse model. We plan to identify the effects of abnormally differentiated adipocytes on LSC proliferation by determining the proliferation rate of LSC surrounded by adipocytes. Furthermore, we intend to investigate the molecular mechanism by which adipocytes impact on LSC proliferation. Leptin, growth hormone and resistin, all of which were overexpressed by adipocytes under stimulation of GDF15, are to be used to test their effect on proliferation of LSC in vitro. We also expect to uncover the signaling pathway of this regulation and verify it clinically. Summarily, this research project intends to elucidate the underlying mechanism by which abnormal BM adipocytes differentiation affects the LSC proliferation and provide a novel insight into the treatment of AML.

白血病干细胞（LSC）恶性功能的维持与骨髓龛密切相关，而急性髓系白血病（AML）骨髓中明显减少的脂肪细胞作为龛的重要组分，如何发挥病理作用知之甚少。我们将脂肪细胞形态学与功能学分析相结合，发现AML骨髓中脂肪细胞存在GDF15介导的分化异常现象。据此推测：脂肪细胞可能通过分化异常参与调控LSC无限增殖功能。本课题拟采用小鼠局部过表达GDF15的髓外骨髓模型，通过比较LSC增殖功能的变化，探讨脂肪细胞分化异常对LSC增殖能力的影响；从前期GDF15干预下脂肪细胞异常分泌的脂肪因子入手，比较脂肪细胞过表达的瘦素、生长激素及抵抗素对LSC增殖能力的影响，结合其所调控的LSC增殖信号通路的筛查，探究分化异常的脂肪细胞对LSC增殖调控的分子机制。最后在临床样本中加以验证。从AML骨髓中脂肪细胞分化异常的新角度探讨LSC恶性增殖功能维持的可能机制，为白血病治疗提供新的思路。

脂肪细胞是骨髓微环境的重要组分，本课题组前期发现急性髓系白血病（AML）患者骨髓脂肪细胞存在异常分化的现象，且GDF15能够参与脂肪细胞的分化。本项目通过体外加入外源性GDF15及体内将敲除GDF15的白血病细胞经尾静脉注入肥胖小鼠，发现GDF15能够调控脂肪细胞的异常分化；通过体外共培养及体内肥胖小鼠的白血病模型进一步发现了分化异常的脂肪细胞能促进白血病细胞的增殖，从脂肪细胞及白血病细胞两个方面初步探讨了其调控白血病细胞增殖的机制可能与脂肪细胞分泌较多的细胞因子及白血病细胞周期的改变有关，为白血病治疗提供新的思路。