Unknown

Dataset Information

0

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


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.

SUBMITTER: Meunier G 

PROVIDER: S-EPMC7581748 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 activi  ...[more]

Similar Datasets

2020-11-11 | PXD016839 | Pride
| S-EPMC5613053 | biostudies-literature
| S-EPMC6878111 | biostudies-literature
| S-EPMC7082118 | biostudies-literature
| S-EPMC9579003 | biostudies-literature
| S-EPMC7453151 | biostudies-literature
2024-06-15 | GSE221459 | GEO
| S-EPMC3432483 | biostudies-literature
| S-EPMC4608389 | biostudies-literature
| S-EPMC7352446 | biostudies-literature