The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.
急性白血病的治疗具有挑战性，因为患者之间及患者体内存在遗传异质性。白血病干细胞（LSCs）相对耐药且易复发。这些细胞的塑性及适应细胞外应激的能力——其中线粒体代谢和自噬起重要作用——进一步使治疗复杂化。磷脂酰肌醇-5-磷酸4-激酶2型蛋白（PIP4K2s）抑制的遗传模型已证明这些酶在线粒体稳态和自噬流中的相关性。本研究揭示了PIP4K2s广谱抑制剂THZ-P1-2在急性白血病细胞中的细胞与分子效应。THZ-P1-2降低了细胞活力，并诱导DNA损伤、细胞凋亡、线粒体膜电位丧失及酸性囊泡细胞器的积累。蛋白表达分析显示THZ-P1-2损害自噬流。此外，THZ-P1-2诱导细胞分化，并与venetoclax产生协同效应。在原代白血病细胞中，基于LC-MS/MS的蛋白质组学分析表明，对THZ-P1-2的敏感性与线粒体代谢、细胞周期、细胞起源（造血干细胞和髓系祖细胞）以及TP53通路相关。在健康CD34+细胞中观察到的THZ-P1-2最小影响提示其具有有利的治疗窗口。本研究为靶向线粒体稳态和自噬的PIP4K2s药理抑制提供了新见解，揭示了一类治疗急性白血病的新型药物。
肿瘤(癌症)患者之家