The c-kit proto-oncogene encodes a receptor tyrosine kinase that is crucial to hematopoiesis, melanogenesis, and gametogeneis. Although the enzymatic activity of the c-kit product (KIT) is regulated by its ligand, both the Val559-->Gly (G559) mutation in the juxtamembrane domain and the Asp814-->Val (V814) mutation in the phosphotransferase domain lead to constitutive activation of KIT. By retroviral infection of hematopoietic progenitor cells with KIT(G559) or KIT(V814), KIT(G559) induced development of granulocyte/macrophage and mast-cell colonies in vitro without the addition of exogenous growth factors. KIT(V814) induced factor-independent growth of various types of hematopoietic progenitor cells, resulting in the development of mixed erythroid/myeloid colonies in addition to granulocyte/macrophage and mast-cell colonies. Furthermore, transplantation of KIT(G559) and KIT(V814)-infected bone marrow cells led to development of acute leukemia in one of 10 and six of 10 transplanted mice, respectively. No mice developed hematologic malignancies after transplantation of wild- type KIT-infected cells. Furthermore, transgenic mice expressing KIT(V814) developed acute leukemia or malignant lymphoma. These results demonstrate a direct role of the mutant KITs, particularly KIT(V814), in tumorigenesis of hematopoietic cells and suggest that similar mutations may contribute to the development of human hematologic malignancies.

We have evaluated the antifungal activity of micafungin in serum by using the disk diffusion method with serum-free and serum-added micafungin standard curves. Serum samples from micafungin-treated patients have been shown to exhibit adequate antifungal activity, which was in proportion to both the applied dose and the actual concentration of micafungin measured by high-performance liquid chromatography. The antifungal activity of micafungin in serum was also confirmed with the broth microdilution method.Micafungin has been shown to bind to serum proteins at a level of 99.8% (13). If the unbound drug contributes to its pharmacological activity (the free-drug hypothesis), only 0.2% of total micafungin would be available to exert antifungal activity in the presence of serum, and the MIC for micafungin in vitro would increase 500-fold. However, several studies have shown that this ratio varies from 4-to 267-fold (6, 7, 11), indicating that the antifungal activities of micafungin in serum may not follow the free-drug hypothesis; instead, observed activities are mostly superior to those predicted. Furthermore, it remains unclear whether these results can be applied to micafungin in a patient's serum. To address this issue, we collected serum samples from micafungin-treated patients and examined the relationship between micafungin concentration and its in vitro antifungal activity in serum.This study was approved by the institutional review board, and informed consent was obtained from each patient. Patients with hematologic malignancies, admitted into Osaka University Medical Hospital, were administered micafungin at a dose of 50 to 300 mg/body once daily. The efficacy of prophylaxis was defined as the absence of proven, probable (EORTC-IFICG/NIAID-MSG) (1), or suspected (unexplained persistent fever and clinical findings) (10) fungal infection, through