化疗耐药性B细胞急性淋巴细胞白血病的代谢规律及其调控机制

化疗耐药是B细胞急性淋巴细胞白血病（B-ALL）治疗面临的主要瓶颈问题之一。代谢活动被发现与白血病命运决定密切相关，但代谢调控是否参与B-ALL化疗耐药的产生还很不清楚。我们前期结合基于NADH/NAD+代谢感受器（SoNar）的单细胞尺度精准代谢研究体系，揭示了急性髓系白血病起始细胞（LICs）的代谢调控规律。据此，我们进一步构建了SoNar转基因小鼠及其B-ALL模型，初步揭示了B-ALL-LICs富集于低SoNar水平（SoNar-low）细胞亚群并以氧化磷酸化为能量来源的新特征；SoNar-low细胞对阿糖胞苷更为耐药且倾向定位于血管周微环境。本项目拟深入探讨小鼠和人耐药性B-ALL细胞代谢特征及其富集功能性LICs的程度；揭示耐药代谢规律与B-ALL细胞微环境定位等命运决定的内在关联和调控机制；解析联合靶向代谢通路对克服耐药的潜在效应，为耐药性B-ALL治疗提供新靶点和策略。

Chemotherapy resistance is one of the major bottlenecks in the treatment of B cell acute lymphoid leukemia (B-ALL). Metabolic activity has been found to be closely related to the cell fates of leukemia, but it is not clear whether metabolic regulation is involved in the occurrence of B-ALL chemotherapy resistance. In combination with the NADH/NAD+ metabolic sensor (SoNar) at the single-cell level, we revealed the unique metabolic characteristics of acute myeloid leukemia initiating cells (LICs). Based on this, we further constructed a SoNar transgenic mouse line and established the B-ALL model with SoNar mice. Our preliminary data showed that B-ALL-LICs were enriched in the cell subpopulation with low SoNar level (SoNar-low) and utilized oxidative phosphorylation as the main energy source. SoNar-low cells were more resistant to the cytarabine treatment and tended to localize in the perivascular niche. This proposal aims to further elucidate the metabolic characteristics of mouse and human chemoresistance B-ALL cells and the extent in the enrichment functional LICs. We will also evaluate the potential connections between the metabolic properties of chemoresistance B-ALL cells and their cell fate determinations including the niche localization, and the potential effects in the treatment of chemoresistance of B-ALL by targeting metabolic pathways with chemotherapeutic drugs. These studies may provide novel targets and promote the development of the therapeutic strategies for the treatment of the chemoresistance B-ALL.