期刊
ONCOGENE
卷 27, 期 29, 页码 4096-4106出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.40
关键词
leukemia; oncogenic transformation; phosphoinositide 3-kinase; signal transduction
Constitutive activation of the phosphoinositide 3-kinase ( PI3K)-AKT pathway is observed in up to 70% of acute myelogenous leukemia. To investigate the relevance of an intrinsic PI3K-AKT pathway activation in hematopoietic malignancies, we analysed the effect of point mutations in the catalytic ( p110 alpha) and regulatory ( p85 alpha) subunit of class IA PI3K. We demonstrated that mutations in the helical ( E542K, E545A) and kinase domain ( H1047R) of p110 alpha constitutively activate the PI3K-AKT pathway and lead to factor-independent growth of early hematopoietic cells. Proliferation and survival of the cells were inhibited in a time- and dose-dependent manner using either PI3K or AKT inhibitors. The mammalian target of rapamycin ( mTOR) was demonstrated to be important for mitogenic, but not antiapoptotic signaling of mutant p110a. In a syngenic mouse model, hematopoietic cells expressing mutated p110 alpha induced a leukemia-like disease characterized by anemia, neoplastic infiltration of hematopoietic organs and 90% mortality within 5 weeks, whereas activated mutants of the receptor tyrosine kinase c-KIT led to 100% mortality within 10 days. Our data show that point mutations in the p110 alpha subunit of class IA PI3K confer factor independence to hematopoietic cells in vitro and leukemogenic potential in vivo, but have lower transforming activity than a deregulated class III receptor tyrosine kinase.
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