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- Title
Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia.
- Authors
Meunier, Godelieve; Birsen, Rudy; Cazelles, Clarisse; Belhadj, Maya; Cantero-Aguilar, Lilia; Kosmider, Olivier; Fontenay, Michaela; Azar, Nabih; Mayeux, Patrick; Chapuis, Nicolas; Tamburini, Jerôme; Bouscary, Didier
- 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.
- Publication
Oncogenesis, 2020, Vol 9, Issue 10, p1
- ISSN
2157-9024
- Publication type
Article
- DOI
10.1038/s41389-020-00278-8