Metabolic data: Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in <em>NOTCH1 </em>that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between <em>NOTCH1</em>, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in <em>NOTCH1</em>-mutated and less so in <em>NOTCH1</em>-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring <em>NOTCH1</em>-mutated T-ALL<em>. </em>We leverage this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.T细胞急性淋巴细胞白血病（T-cell acute lymphoblastic leukemia, T-ALL）通常由激活型NOTCH1（NOTCH1）突变驱动，该突变可促进谷氨酰胺氧化。本研究鉴定出氧化磷酸化（oxidative phosphorylation, OxPhos）是白血病细胞存活的关键通路，并证实NOTCH1、升高的OxPhos基因表达与前白血病及白血病模型中获得性化疗耐药存在直接关联。采用线粒体复合物I抑制剂IACS-010759干扰OxPhos，可通过诱导代谢停滞与氧化还原失衡，对NOTCH1突变型T-ALL细胞产生强效生长抑制，而对NOTCH1野生型（NOTCH1-wt）T-ALL细胞的抑制效果较弱。从机制上讲，OxPhos抑制会诱导代谢重编程转向谷氨酰胺分解代谢。我们证实，联合使用OxPhos药理学阻断剂与谷氨酰胺酶（glutaminase，关键谷氨酰胺代谢酶）的诱导性敲低，可在携带NOTCH1突变型T-ALL的小鼠中引发协同致死效应。我们借助这一协同致死相互作用证实：将IACS-010759与含L-天冬酰胺酶（L-asparaginase）的化疗方案联用——L-天冬酰胺酶可揭示白血病细胞的谷氨酰胺依赖性——能够降低谷氨酰胺分解代谢水平，并在人类T-ALL临床前模型中实现显著的肿瘤缩小。综上，T-ALL对OxPhos的这一代谢依赖性为其提供了合理的治疗靶点。