TY - JOUR
T1 - MTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells
AU - Chen, Weina
AU - Drakos, Elias
AU - Grammatikakis, Ioannis
AU - Schlette, Ellen J.
AU - Li, Jiang
AU - Leventaki, Vasiliki
AU - Staikou-Drakopoulou, Efi
AU - Patsouris, Efstratios
AU - Panayiotidis, Panayiotis
AU - Medeiros, L. Jeffrey
AU - Rassidakis, George Z.
N1 - Funding Information:
This study was funded by the NIH Joe Moakley Leukemia SPORE grant to The University of Texas M.D. Anderson Cancer Center. G.Z. Rassidakis is a recipient of a Leukemia SPORE Developmental Research Award.
PY - 2010/11/10
Y1 - 2010/11/10
N2 - 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.
AB - 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.
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U2 - 10.1186/1476-4598-9-292
DO - 10.1186/1476-4598-9-292
M3 - Article
C2 - 21067588
AN - SCOPUS:78149237281
SN - 1476-4598
VL - 9
JO - Molecular Cancer
JF - Molecular Cancer
M1 - 292
ER -