Role of intracellular tyrosines in activating KIT-induced myeloproliferative disease.
Leukemia
; 26(7): 1499-1506, 2012 Jul.
Article
in En
| MEDLINE
| ID: mdl-22297723
ABSTRACT
Gain-of-function mutations in KIT receptor in humans are associated with gastrointestinal stromal tumors, systemic mastocytosis and acute myelogenous leukemia. The intracellular signals that contribute to oncogenic KIT-induced myeloproliferative disease (MPD) are poorly understood. Here, we show that oncogenic KITD814V-induced MPD occurs in the absence of ligand stimulation. The intracellular tyrosine residues are important for KITD814V-induced MPD, albeit to varying degrees. Among the seven intracellular tyrosines examined, tyrosine 719 alone has a unique role in regulating KITD814V-induced proliferation and survival in vitro, and MPD in vivo. Importantly, the extent to which AKT, extracellular signal-regulated kinase and Stat5 signaling pathways are activated via the seven intracellular tyrosines in KITD814V impacts the latency of MPD and severity of the disease. Our results identify critical signaling molecules involved in regulating KITD814V-induced MPD, which might be useful for developing novel therapeutic targets for hematologic malignancies involving this mutation.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tyrosine
/
Signal Transduction
/
Proto-Oncogene Proteins c-kit
/
Mutation
/
Myeloproliferative Disorders
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Leukemia
Journal subject:
HEMATOLOGIA
/
NEOPLASIAS
Year:
2012
Type:
Article
Affiliation country:
India