Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. Vacuolar protein sorting 34 (VPS34) is a member of the phosphatidylinositol-3-kinase lipid kinase family that controls the canonical autophagy pathway and vesicular trafficking. Using a recently developed specific inhibitor (VPS34-IN1), we found that VPS34 inhibition induces apoptosis in AML cells but not in normal CD34+ hematopoietic cells. Complete and acute inhibition of VPS34 was required for the antileukemic activity of VPS34-IN1. This inhibitor also has pleiotropic effects against various cellular functions related to class III PI3K in AML cells that may explain their survival impairment. VPS34-IN1 inhibits basal and l-asparaginase-induced autophagy in AML cells. A synergistic cell death activity of this drug was also demonstrated. VPS34-IN1 was additionally found to impair vesicular trafficking and mTORC1 signaling. From an unbiased approach based on phosphoproteomic analysis, we identified that VPS34-IN1 specifically inhibits STAT5 phosphorylation downstream of FLT3-ITD signaling in AML. The identification of the mechanisms controlling FLT3-ITD signaling by VPS34 represents an important insight into the oncogenesis of AML and could lead to new therapeutic strategies.

急性髓细胞性白血病（AML）是一种侵袭性疾病，预后较差。液泡蛋白分选34（VPS34）是磷脂酰肌醇3激酶脂质激酶家族的成员，该家族控制典型的自噬途径和囊泡运输。使用最近开发的特异性抑制剂（VPS34-IN1），我们发现VPS34抑制可诱导AML细胞凋亡，但不会诱导正常CD34 +造血细胞凋亡。VPS34-IN1的抗白血病活性需要完全和急性抑制VPS34。这种抑制剂还对AML细胞中与III类PI3K相关的多种细胞功能具有多效作用，这可能解释了它们的生存障碍。VPS34-IN1抑制基础和升-天冬酰胺酶诱导的AML细胞自噬。还显示了该药物的协同细胞死亡活性。还发现VPS34-IN1损害了水泡运输和mTORC1信号传导。从基于磷酸化蛋白质组学分析的无偏见方法中，我们发现VPS34-IN1特异性抑制AML中FLT3-ITD信号传导下游的STAT5磷酸化。通过VPS34控制FLT3-ITD信号传导的机制的鉴定代表了对AML发生的重要了解，并可能导致新的治疗策略。