A direct role of the mutant c-kit in ligand-independent mast cell growth, tumorigenesis in vivo, and mast cell differentiation has been demonstrated in murine systems using either retroviral infection of hematopoietic progenitor cells with KIT D814V, 13 or the transfection of KIT D814Y cDNA into the murine IL3-dependent mast cell line IC2. 14, 15 With regards to human mutations, only the functional effects of D816V have been investigated. Transfection of D816V KIT cDNA into mybtransformed granulocyte-macrophage colony stimulating factor (GM-CSF)-dependent early murine myeloid cells has been shown to lead to factor independence, increased survival of immature and mature cells, tumorigenicity, and a differentiation resembling that previously noted only in the IC-2 mast cell line. 11

It is worth noting that 3 of the 6 patients positive for c-kit mutations, namely patient 1 with t (8; 21) AML-M2, and patients 13 and 15 both with inv (16) AML-M4Eo, showed bone marrow mast cell (BMMC) involvement. Mast cell differentiation was massive in patient 1, who carried the Asp816Tyr mutation in 100% of the blasts. 9, 16 Patients 13 and 15 carrying the Asp816Val mutation had clusters of BMMCs characterized by polar nuclei, a reduced number of small granules, and large empty vacuoles. The remaining three patients positive for Asp816Val did not show any significant increase in BMMCs. The data provided here show that c-kit mutations are not such a rare event in CBF leukemias that display a highly significant correlation for CD117 positivity. In order to assess the true frequency of c-kit mutations in these AML subtypes, scanning of the whole c-kit gene should be performed on a larger sample of patients. Further studies will help elucidate whether c-kit mutations are a secondarily acquired event, as suggested