骨髓脂肪细胞异常分化在急性T淋巴细胞白血病微小残留病中的作用及机制研究

Minimal residual disease (MRD) is the important reason for refractory and relapse of T-acute lymphoblastic leukemia (T-ALL), thus it is of great significance to explore the pathogenesis and eliminating strategy of MRD in T-ALL. We found that chemotherapy can promote bone marrow mesenchymal stem cells (BMSCs) from T-ALL patients to disdifferentiate into adipocytes which can further enhance the survival and chemo-resistance of T-ALL cells. After chemotherapy, the expression of DLL4 in BMSCs-derived adipocytes was obviously increased, the Notch1 pathway was further activated and the expression of downstream lipid metabolism-related molecule FABP4 was also elevated. Therefore, we speculate that bone marrow adipocyte disdifferentiation after chemotherapy in T-ALL patients mediates the survival and chemo-resistance of residual T-ALL cells through DLL4/Notch1 signaling pathway. In the following study, we intend to investigate the mechanisms of bone marrow adipocyte disdifferentiation after chemotherapy and clarify our hypothesis that BMSCs-derived adipocytes regulate lipid metabolism to protect residual T-ALL cells through DLL4/Notch1 signaling pathway. Our study is of great importance in revealing the mechanisms of MRD and provides a novel strategy for eliminating MRD in T-ALL.

急性T淋巴细胞白血病（T-ALL）难治、复发的重要原因之一是微小残留病（MRD）的存在，探寻其发生机制及清除策略具有重要意义。我们发现T-ALL患者化疗后骨髓间充质干细胞（BMSCs）向脂肪细胞异常分化，并能促进T-ALL细胞耐药；化疗药物作用于BMSCs后，其分化成的脂肪细胞表面Notch配体DLL4表达明显增高，T-ALL细胞中Notch1通路进一步激活，下游脂代谢分子FABP4表达升高。因此，我们推测T-ALL化疗后BMSCs向脂肪细胞异常分化，可能通过DLL4/Notch1通路介导残留白血病细胞的存活及耐药。本项目拟在前期工作基础上，通过体外研究及动物实验明确T-ALL化疗后骨髓脂肪细胞异常分化的具体机制，证实其通过DLL4/Notch1通路调控脂代谢，从而发挥对残留白血病细胞的保护作用。预期目标的实现将揭示T-ALL MRD形成的新机制，为清除MRD提供新策略。

急性T淋巴细胞白血病（T-ALL）难治、复发的重要原因之一是微小残留病（MRD）的存在，探寻MRD发生机制及清除策略具有重要的临床意义。本项目研究发现T-ALL患者化疗后骨髓微环境中脂肪细胞明显增多；体外培养诱导BMSCs成脂分化实验发现，经典化疗药物地塞米松（DEX）和去乙酰化酶抑制剂（HDACi）类药物可明显促进骨髓间充质干细胞（BMSCs）向脂肪方向异常分化；为探究其机制，我们应用RNA-Seq分析化疗药物诱导BMSCs脂化过程中的差异表达分子，发现SREBF1表达明显升高；抑制SREBF1的表达或作用可逆转HDACi对BMSCs向脂肪细胞分化的促进作用，说明HDACi可通过调控SREBF1促进BMSCs向脂肪细胞异常分化。此外，我们发现化疗后BMSCs来源的脂肪细胞可降低T-ALL细胞的药物敏感性、促进细胞增殖以及增强细胞的粘附力，对T-ALL细胞起保护作用。脂肪细胞通过释放CXCL13趋化因子将T-ALL细胞募集到自身周围，然后通过DLL1/Notch1受体配体结合激活T-ALL细胞中的Notch1信号通路，从而促进T-ALL细胞的存活及耐药。应用SREBF1抑制剂可阻断BMSCs的脂化过程，逆转BMSCs来源的脂肪细胞对T-ALL细胞的保护作用。本研究揭示了化疗后BMSCs成脂分化异常介导T-ALL MRD的新机制，为清除T-ALL MRD提供了新靶点，具有潜在的临床应用前景。