PMID- 21067588
OWN - NLM
STAT- MEDLINE
DCOM- 20110120
LR  - 20211203
IS  - 1476-4598 (Electronic)
IS  - 1476-4598 (Linking)
VI  - 9
DP  - 2010 Nov 10
TI  - mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated 
      acute myeloid leukemia cells.
PG  - 292
LID - 10.1186/1476-4598-9-292 [doi]
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.
FAU - Chen, Weina
AU  - Chen W
AD  - Department of Hematopathology, The University of Texas M.D. Anderson Cancer 
      Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA.
FAU - Drakos, Elias
AU  - Drakos E
FAU - Grammatikakis, Ioannis
AU  - Grammatikakis I
FAU - Schlette, Ellen J
AU  - Schlette EJ
FAU - Li, Jiang
AU  - Li J
FAU - Leventaki, Vasiliki
AU  - Leventaki V
FAU - Staikou-Drakopoulou, Efi
AU  - Staikou-Drakopoulou E
FAU - Patsouris, Efstratios
AU  - Patsouris E
FAU - Panayiotidis, Panayiotis
AU  - Panayiotidis P
FAU - Medeiros, L Jeffrey
AU  - Medeiros LJ
FAU - Rassidakis, George Z
AU  - Rassidakis GZ
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20101110
PL  - England
TA  - Mol Cancer
JT  - Molecular cancer
JID - 101147698
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Ribosomal Protein S6)
RN  - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/immunology/metabolism
MH  - Apoptosis/genetics/physiology
MH  - Blotting, Western
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cell Survival/genetics/physiology/radiation effects
MH  - Humans
MH  - Immunohistochemistry
MH  - Leukemia, Myeloid, Acute/*enzymology/genetics
MH  - Phosphoproteins/genetics/immunology/metabolism
MH  - Ribosomal Protein S6/immunology/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/immunology/metabolism
MH  - Signal Transduction/genetics/physiology
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Tumor Cells, Cultured
MH  - fms-Like Tyrosine Kinase 3/genetics/*metabolism
PMC - PMC2993677
EDAT- 2010/11/12 06:00
MHDA- 2011/01/21 06:00
PMCR- 2010/11/10
CRDT- 2010/11/12 06:00
PHST- 2010/05/17 00:00 [received]
PHST- 2010/11/10 00:00 [accepted]
PHST- 2010/11/12 06:00 [entrez]
PHST- 2010/11/12 06:00 [pubmed]
PHST- 2011/01/21 06:00 [medline]
PHST- 2010/11/10 00:00 [pmc-release]
AID - 1476-4598-9-292 [pii]
AID - 10.1186/1476-4598-9-292 [doi]
PST - epublish
SO  - Mol Cancer. 2010 Nov 10;9:292. doi: 10.1186/1476-4598-9-292.