PMID- 15178581
OWN - NLM
STAT- MEDLINE
DCOM- 20041006
LR  - 20210206
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 104
IP  - 6
DP  - 2004 Sep 15
TI  - Identifying and characterizing a novel activating mutation of the FLT3 tyrosine 
      kinase in AML.
PG  - 1855-8
AB  - The FLT3 receptor is activated by juxtamembrane insertion mutations and by 
      activation loop point mutations in patients with acute myeloid leukemia (AML). In 
      a systematic tyrosine kinase gene exon resequencing study, 21 of 24 FLT3 exons 
      were sequenced in samples from 53 patients with AML, 9 patients with acute 
      lymphoblastic leukemia (ALL), and 3 patients with myelodysplasia samples. Three 
      patients had novel point mutations at residue N841 that resulted in a change to 
      isoleucine in 2 samples and to tyrosine in 1 sample. Introduction of FLT3-N841I 
      cDNA into Ba/F3 cells led to interleukin-3 (IL-3)-independent proliferation, 
      receptor phosphorylation, and constitutive activation of signal transducer and 
      activator of transcription 5 (STAT5) and extracellular regulatory kinase (ERK), 
      suggesting that the N841I mutation confers constitutive activity to the receptor. 
      An FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC(50) 
      10 nM), but not of wild-type Ba/F3 cells cultured with IL-3. PKC412 also reduced 
      tyrosine phosphorylation of the mutant receptor and inhibited STAT5 
      phosphorylation. Examination of the FLT3 autoinhibited structure showed that N841 
      is the key residue in a hydrogen-bonding network that likely stabilizes the 
      activation loop. These results suggest that mutations at N841 represent a 
      significant new activating mutation in patients with AML and that patients with 
      such mutations may respond to small-molecule FLT3 inhibitors such as PKC412.
FAU - Jiang, Jingrui
AU  - Jiang J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, 
      D720C, Boston, MA 02115, USA.
FAU - Paez, J Guillermo
AU  - Paez JG
FAU - Lee, Jeffrey C
AU  - Lee JC
FAU - Bo, Ronghai
AU  - Bo R
FAU - Stone, Richard M
AU  - Stone RM
FAU - DeAngelo, Daniel J
AU  - DeAngelo DJ
FAU - Galinsky, Ilene
AU  - Galinsky I
FAU - Wolpin, Brian M
AU  - Wolpin BM
FAU - Jonasova, Anna
AU  - Jonasova A
FAU - Herman, Paula
AU  - Herman P
FAU - Fox, Edward A
AU  - Fox EA
FAU - Boggon, Titus J
AU  - Boggon TJ
FAU - Eck, Michael J
AU  - Eck MJ
FAU - Weisberg, Ellen
AU  - Weisberg E
FAU - Griffin, James D
AU  - Griffin JD
FAU - Gilliland, D Gary
AU  - Gilliland DG
FAU - Meyerson, Matthew
AU  - Meyerson M
FAU - Sellers, William R
AU  - Sellers WR
LA  - eng
GR  - C66996/PHS HHS/United States
GR  - DK50654/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040603
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Interleukin-3)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.10.1 (FLT3 protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
RN  - H88EPA0A3N (Staurosporine)
RN  - ID912S5VON (midostaurin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Cell Division/drug effects
MH  - Enzyme Activation
MH  - Female
MH  - Humans
MH  - Hydrogen Bonding
MH  - Interleukin-3/pharmacology
MH  - Leukemia, Myeloid, Acute/*enzymology/*genetics/metabolism/pathology
MH  - Male
MH  - Middle Aged
MH  - Models, Molecular
MH  - Mutation/*genetics
MH  - Phosphorylation
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Proteins/chemistry/*genetics/*metabolism
MH  - Receptor Protein-Tyrosine Kinases/chemistry/*genetics/*metabolism
MH  - Signal Transduction
MH  - Staurosporine/*analogs & derivatives/pharmacology
MH  - fms-Like Tyrosine Kinase 3
EDAT- 2004/06/05 05:00
MHDA- 2004/10/07 09:00
CRDT- 2004/06/05 05:00
PHST- 2004/06/05 05:00 [pubmed]
PHST- 2004/10/07 09:00 [medline]
PHST- 2004/06/05 05:00 [entrez]
AID - S0006-4971(20)43434-2 [pii]
AID - 10.1182/blood-2004-02-0712 [doi]
PST - ppublish
SO  - Blood. 2004 Sep 15;104(6):1855-8. doi: 10.1182/blood-2004-02-0712. Epub 2004 Jun 
      3.