To explore the genetic abnormalities that cooperate with AML1-ETO (AE) fusion gene in the pathogenesis of acute myeloid leukemia (AML) with t(8; 21), we undertook to screen for a number of candidate genes and identified a high frequency mutation of proto-oncogene C-KIT (25/53 cases, 47%). This event seems to be specific to t(8;21) leukemia since no mutation was detected in 57 patients with other types of leukemia. Totally eleven types of mutations were characterized and 6 ones including 3 point mutations in the tyrosine kinase (TK) domain and three types of internal tandem duplication (ITD) in the juxtamembrane (JM) or extracellular (EC) domains were discovered for the first time. Bioinformatics analysis revealed all these mutations might favor the activation of the C-KIT, as proven by TK activity assay. Patients with a mutant C-KIT (mC-KIT) allele had a higher white blood cell count and a poorer prognosis than those bearing wild-type C-KIT. The expression of C-KIT at both mRNA and protein levels was higher in t(8;21) leukemia patients than most other leukemia types. In addition, the TK inhibitor Gleevec suppressed the C-KIT activity, inhibited the proliferation and induced apoptosis of t(8;21) leukemic cells bearing C-KIT mutation or over-expression. Our study thus provides strong evidence to the model of leukemogenesis which requires a cooperation of cytosolic signaling and transcription factor for a full-blown leukemia phenotype to display.

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