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Meunier G, Birsen R, Cazelles C, et al. Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia. Oncogenesis. 2020;9(10):94doi: 10.1038/s41389-020-00278-8.
Meunier, G., Birsen, R., Cazelles, C., Belhadj, M., Cantero-Aguilar, L., Kosmider, O., Fontenay, M., Azar, N., Mayeux, P., Chapuis, N., Tamburini, J., & Bouscary, D. (2020). Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia. Oncogenesis, 9(10), 94. https://doi.org/10.1038/s41389-020-00278-8
Meunier, Godelieve, et al. "Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia." Oncogenesis vol. 9,10 (2020): 94. doi: https://doi.org/10.1038/s41389-020-00278-8
Meunier G, Birsen R, Cazelles C, Belhadj M, Cantero-Aguilar L, Kosmider O, Fontenay M, Azar N, Mayeux P, Chapuis N, Tamburini J, Bouscary D. Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia. Oncogenesis. 2020 Oct 22;9(10):94. doi: 10.1038/s41389-020-00278-8. PMID: 33093450; PMCID: PMC7581748.
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Oncogenesis. 2020 Oct 22;9(10):94. doi: 10.1038/s41389-020-00278-8.

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

Oncogenesis

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

Affiliations

  1. Institut Cochin, Université de Paris, CNRS UMR8104, INSERM U1016, Paris, France.
  2. Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
  3. Service d'hématologie Clinique, Hôpital Cochin, APHP, Paris, France.
  4. Service d'hématologie Biologique, Hôpital Cochin, APHP, Paris, France.
  5. Service d'hémobiothérapie, Hôpital La Pitié Salpétrière, APHP, Paris, France.
  6. Proteomic core facility of Paris Descartes University (3P5), Paris, France.
  7. Institut Cochin, Université de Paris, CNRS UMR8104, INSERM U1016, Paris, France. [email protected].
  8. Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. [email protected].
  9. Service d'hématologie Clinique, Hôpital Cochin, APHP, Paris, France. [email protected].

PMID: 33093450 PMCID: PMC7581748 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.

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