MTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells

Weina Chen, Elias Drakos, Ioannis Grammatikakis, Ellen J. Schlette, Jiang Li, Vasiliki Leventaki, Efi Staikou-Drakopoulou, Efstratios Patsouris, Panayiotis Panayiotidis, L. Jeffrey Medeiros, George Z. Rassidakis

Research output: Contribution to journalArticle

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Abstract

Activating mutations of the FLT3 gene mediate leukemogenesis, at least in part, through activation of PI3K/AKT. The mammalian target of rapamycin (mTOR)-Raptor signaling pathway is known to act downstream of AKT. Here we show that the mTOR effectors, 4EBP1, p70S6K and rpS6, are highly activated in cultured and primary FLT3-mutated acute myeloid leukemia (AML) cells. Introduction of FLT3-ITD expressing constitutively activated FLT3 kinase further activates mTOR and its downstream effectors in BaF3 cells. We also found that mTOR signaling contributes to tumor cell survival, as demonstrated by pharmacologic inhibition of PI3K/AKT/mTOR, or total silencing of the mTOR gene. Furthermore, inhibition of FLT3 kinase results in downregulation of mTOR signaling associated with decreased survival of FLT3-mutated AML cells. These findings suggest that mTOR signaling operates downstream of activated FLT3 kinase thus contributing to tumor cell survival, and may represent a promising therapeutic target for AML patients with mutated-FLT3.

Original languageEnglish (US)
Article number292
JournalMolecular Cancer
Volume9
DOIs
StatePublished - Nov 10 2010

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Myeloid Cells
Sirolimus
Acute Myeloid Leukemia
Phosphotransferases
Survival
Phosphatidylinositol 3-Kinases
Cell Survival
Raptors
70-kDa Ribosomal Protein S6 Kinases
Genes
Neoplasms
Down-Regulation
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology

Cite this

Chen, W., Drakos, E., Grammatikakis, I., Schlette, E. J., Li, J., Leventaki, V., ... Rassidakis, G. Z. (2010). MTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. Molecular Cancer, 9, [292]. https://doi.org/10.1186/1476-4598-9-292

MTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. / Chen, Weina; Drakos, Elias; Grammatikakis, Ioannis; Schlette, Ellen J.; Li, Jiang; Leventaki, Vasiliki; Staikou-Drakopoulou, Efi; Patsouris, Efstratios; Panayiotidis, Panayiotis; Medeiros, L. Jeffrey; Rassidakis, George Z.

In: Molecular Cancer, Vol. 9, 292, 10.11.2010.

Research output: Contribution to journalArticle

Chen, W, Drakos, E, Grammatikakis, I, Schlette, EJ, Li, J, Leventaki, V, Staikou-Drakopoulou, E, Patsouris, E, Panayiotidis, P, Medeiros, LJ & Rassidakis, GZ 2010, 'MTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells', Molecular Cancer, vol. 9, 292. https://doi.org/10.1186/1476-4598-9-292
Chen, Weina ; Drakos, Elias ; Grammatikakis, Ioannis ; Schlette, Ellen J. ; Li, Jiang ; Leventaki, Vasiliki ; Staikou-Drakopoulou, Efi ; Patsouris, Efstratios ; Panayiotidis, Panayiotis ; Medeiros, L. Jeffrey ; Rassidakis, George Z. / MTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. In: Molecular Cancer. 2010 ; Vol. 9.
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