Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia

Godelieve Meunier,Michaela Fontenay,Olivier Kosmider,Patrick Mayeux,Maya Belhadj,Lilia Cantero-Aguilar,Jerôme Tamburini,Nabih Azar,Rudy Birsen,Clarisse Cazelles,Didier Bouscary,Nicolas Chapuis

doi:10.1038/s41389-020-00278-8

Abstract

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.

Highlights

Acute myeloid leukemia (AML) is an aggressive disease caused by the transformation of hematopoietic progenitor cells due to acquired genetic alterations[1]
Vacuolar protein sorting 34 (VPS34)-IN1 was further found to induce the dosedependent cleavage of PARP, caspase-3, and caspase-8 proteins (Fig. 1E) and dose-dependent mitochondrial depolarization, as revealed by TMRE staining (Fig. 1F). These results demonstrated that VPS34 IN1 induces mitochondrial apoptotic cell death in AML cells
We demonstrate that VPS34-IN1 causes pleiotropic effects on various cellular functions related to class III PI3K in AML cells, and that this may explain their survival impairment upon exposure to this inhibitor (Supplemental Fig. 4)

Summary

Introduction

Acute myeloid leukemia (AML) is an aggressive disease caused by the transformation of hematopoietic progenitor cells due to acquired genetic alterations[1]. New therapies for AML have emerged in recent years, the prognosis remains poor and new therapeutic strategies are needed[2]. Vacuolar protein sorting 34 (VPS34) is a member of the phosphatidylinositol-3-kinase lipid kinase family. VPS34 binds to a regulatory subunit (VPS15) to form the only class III PI3K present in mammalian cells. This class III PI3K uses phosphatidylinositol (PIP) as a substrate to produce PI3P. VPS34 is crucial for key cellular functions such as autophagy, endocytic sorting, phagocytosis, and cell signaling[4,5]

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Conclusion