高代谢灵活性对于急性髓系白血病（AML）的持续存在和治疗耐药至关重要。在 20-30% 的 AML 患者中，FLT3 的激活突变，特别是 FLT3-ITD，是关键的治疗靶点。在这里，我们研究了 FLT3-ITD 对 AML 代谢的影响。核磁共振 (NMR) 分析显示丙酮酸向三羧酸 (TCA) 循环的重组增强，表明丙酮酸脱氢酶复合物 (PDC) 的活性增加。一致的是，FLT3-ITD 阳性细胞表达高水平的 PDP1（PDC 激活剂）。将 PDP1 的内源标记与全基因组 CRISPR 筛选相结合表明，FLT3-ITD 通过 RAS 信号轴诱导 PDP1 表达。 PDP1 敲低导致细胞呼吸减少，从而仅损害 FLT3-ITD 细胞的增殖。即使在缺氧条件下，这些细胞仍继续依赖于 PDP1，并且与 FLT3-ITD 阴性细胞不同，它们在复氧过程中表现出快速、依赖 PDP1 的呼吸能力恢复。此外，我们发现 PDP1 可以改变对 FLT3 抑制的反应。与 FLT3 酪氨酸激酶抑制剂 quizartinib (AC220) 一起孵育后，PDP1 持续存在或上调，导致葡萄糖/丙酮酸代谢进一步转向 TCA 循环。在体内 AC220 耐药的 AML 患者的细胞系和外周原始细胞中，PDP1 的过表达增强，而 PDP1 耗竭则降低了 AC220 耐药性。总之，FLT3-ITD 确保 PDP1 的表达，PDP1 是增强氧化葡萄糖代谢和耐药性的关键代谢调节因子。因此，PDP1 成为 AML 管理中的潜在目标漏洞。© 2023。作者。

High metabolic flexibility is pivotal for the persistence and therapy resistance of acute myeloid leukemia (AML). In 20-30% of AML patients, activating mutations of FLT3, specifically FLT3-ITD, are key therapeutic targets. Here, we investigated the influence of FLT3-ITD on AML metabolism. Nuclear Magnetic Resonance (NMR) profiling showed enhanced reshuffling of pyruvate towards the tricarboxylic acid (TCA) cycle, suggesting an increased activity of the pyruvate dehydrogenase complex (PDC). Consistently, FLT3-ITD-positive cells expressed high levels of PDP1, an activator of the PDC. Combining endogenous tagging of PDP1 with genome-wide CRISPR screens revealed that FLT3-ITD induces PDP1 expression through the RAS signaling axis. PDP1 knockdown resulted in reduced cellular respiration thereby impairing the proliferation of only FLT3-ITD cells. These cells continued to depend on PDP1, even in hypoxic conditions, and unlike FLT3-ITD-negative cells, they exhibited a rapid, PDP1-dependent revival of their respiratory capacity during reoxygenation. Moreover, we show that PDP1 modifies the response to FLT3 inhibition. Upon incubation with the FLT3 tyrosine kinase inhibitor quizartinib (AC220), PDP1 persisted or was upregulated, resulting in a further shift of glucose/pyruvate metabolism towards the TCA cycle. Overexpression of PDP1 enhanced, while PDP1 depletion diminished AC220 resistance in cell lines and peripheral blasts from an AC220-resistant AML patient in vivo. In conclusion, FLT3-ITD assures the expression of PDP1, a pivotal metabolic regulator that enhances oxidative glucose metabolism and drug resistance. Hence, PDP1 emerges as a potentially targetable vulnerability in the management of AML.© 2023. The Author(s).