PMID- 16597595
OWN - NLM
STAT- MEDLINE
DCOM- 20061005
LR  - 20211203
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 108
IP  - 3
DP  - 2006 Aug 1
TI  - Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells.
PG  - 1065-72
AB  - Two classes of oncogenic mutations of the c-kit tyrosine kinase have been 
      described: the juxtamembrane domain V560G mutation, which is preferentially found 
      in gastrointestinal stromal tumors (GISTs), and the kinase domain D816V mutation, 
      which is highly representative of systemic mastocytosis (SM). Here we show that 
      both mutations constitutively activate the mammalian target of rapamycin (mTOR) 
      signaling pathway. Surprisingly, the mTOR inhibitor rapamycin induces only 
      apoptosis in HMC-1 cells bearing the D816V but not the V560G mutation. In support 
      of this unexpected selectivity, rapamycin inhibits the phosphorylation of 4E-BP1, 
      a downstream substrate of the mTOR pathway, but only in D816V HMC-1 cells. 
      Importantly, D816V mast cells isolated from SM patients or from transgenic mice 
      are sensitive to rapamycin whereas normal human or mouse mast cells are not. 
      Thus, rapamycin inhibition appears specific to the D816V mutation. At present 
      there is no effective cure for SM patients with the D816V mutation. The data 
      presented here provide a rationale to test whether rapamycin could be a possible 
      treatment for SM and other hematologic malignancies with the D816V mutation.
FAU - Gabillot-Carre, Marion
AU  - Gabillot-Carre M
AD  - CNRS UMR-8147, Universite Rene Descartes Paris V, Hopital Necker, 161 rue de 
      Sevres, 75743 Paris cedex 15, France.
FAU - Lepelletier, Yves
AU  - Lepelletier Y
FAU - Humbert, Martine
AU  - Humbert M
FAU - de Sepuvelda, Paulo
AU  - de Sepuvelda P
FAU - Hamouda, Nadine Ben
AU  - Hamouda NB
FAU - Zappulla, Jean Pierre
AU  - Zappulla JP
FAU - Liblau, Roland
AU  - Liblau R
FAU - Ribadeau-Dumas, Antoine
AU  - Ribadeau-Dumas A
FAU - Machavoine, Francois
AU  - Machavoine F
FAU - Letard, Sebastien
AU  - Letard S
FAU - Baude, Cedric
AU  - Baude C
FAU - Hermant, Aurelie
AU  - Hermant A
FAU - Yang, Ying
AU  - Yang Y
FAU - Vargaftig, Jacques
AU  - Vargaftig J
FAU - Bodemer, Christine
AU  - Bodemer C
FAU - Morelon, Emmanuel
AU  - Morelon E
FAU - Lortholary, Olivier
AU  - Lortholary O
FAU - Recher, Christian
AU  - Recher C
FAU - Laurent, Guy
AU  - Laurent G
FAU - Dy, Michel
AU  - Dy M
FAU - Arock, Michel
AU  - Arock M
FAU - Dubreuil, Patrice
AU  - Dubreuil P
FAU - Hermine, Olivier
AU  - Hermine O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060404
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Humans
MH  - Mast Cells/drug effects/pathology
MH  - Mastocytosis, Systemic/*drug therapy/*genetics/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - *Mutation, Missense
MH  - *Pharmacogenetics
MH  - Protein Kinases/metabolism
MH  - Proto-Oncogene Proteins c-kit/*genetics
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Cells, Cultured
EDAT- 2006/04/07 09:00
MHDA- 2006/10/06 09:00
CRDT- 2006/04/07 09:00
PHST- 2006/04/07 09:00 [pubmed]
PHST- 2006/10/06 09:00 [medline]
PHST- 2006/04/07 09:00 [entrez]
AID - S0006-4971(20)52764-X [pii]
AID - 10.1182/blood-2005-06-2433 [doi]
PST - ppublish
SO  - Blood. 2006 Aug 1;108(3):1065-72. doi: 10.1182/blood-2005-06-2433. Epub 2006 Apr 
      4.