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

doi:10.1186/1476-4598-9-292

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

Mol Cancer. 2010 Nov 10:9:292. doi: 10.1186/1476-4598-9-292.

Authors

Weina Chen¹, Elias Drakos, Ioannis Grammatikakis, Ellen J Schlette, Jiang Li, Vasiliki Leventaki, Efi Staikou-Drakopoulou, Efstratios Patsouris, Panayiotis Panayiotidis, L Jeffrey Medeiros, George Z Rassidakis

Affiliation

¹ Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / immunology
Adaptor Proteins, Signal Transducing / metabolism
Apoptosis / genetics
Apoptosis / physiology
Blotting, Western
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
Cell Survival / genetics
Cell Survival / physiology
Cell Survival / radiation effects
Humans
Immunohistochemistry
Leukemia, Myeloid, Acute / enzymology*
Leukemia, Myeloid, Acute / genetics
Phosphoproteins / genetics
Phosphoproteins / immunology
Phosphoproteins / metabolism
Ribosomal Protein S6 / immunology
Ribosomal Protein S6 / metabolism
Ribosomal Protein S6 Kinases, 70-kDa / immunology
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Signal Transduction / genetics
Signal Transduction / physiology
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Tumor Cells, Cultured
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
EIF4EBP1 protein, human
Phosphoproteins
Ribosomal Protein S6
fms-Like Tyrosine Kinase 3
Ribosomal Protein S6 Kinases, 70-kDa
TOR Serine-Threonine Kinases