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

Autor: 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
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Oncogenesis
Oncogenesis, Vol 9, Iss 10, Pp 1-14 (2020)
ISSN: 2157-9024
Popis: 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.
Databáze: OpenAIRE
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