Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase

Abstract

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.

Functional and phenotypic studies of two variants of a human mast cell line with a distinct set of mutations in the c‐kit proto‐oncogene

“…Corresponding mutations in mouse, c-kit G559 and c-kit V814 have been reported to activate Kit in a SCF independent manner in transfected cells and may alter Kit substrate specificity. 26,[33][34][35]47 HMC-1 560 cells were found to be heterozygous for c-kit G560 but negative for c-kit V816 . In contrast, HMC-1 560,816 cells were heterozygous for both mutations (Figs 4 and 5).…”

“…Val substitution into the Kit receptor, which makes the receptor constitutively phosphorylated and active. 26,[33][34][35] The V816 mutation is especially common in patients with adult onset sporadic mastocytosis and in patients in which mastocytosis is associated with hematologic disorders such as myelodysplastic or myeloproliferative syndromes. [28][29][30] Mutations in other regions of Kit are rare in mastocytosis, although there is a report of two mastocytosis patients with a mutation (G560) in the juxtamembrane region between the transmembrane and tyrosine kinase part of Kit.…”

Mastocytosis cells bearing a c‐kit activating point mutation are characterized by hypersensitivity to stem cell factor and increased apoptosis

“…Changes in mean mast±basophil colony-forming units (mast/bas-CFU) in duplicate clonogenic assays of patient and controls with increasing concentrations of stem cell factor (expressed as a percentage related to identical cultures with interleukin 3, granulocyte colony-stimulating factor and erythropoietin, but without stem cell factor, and using zero amount in the culture without stem cell factor as the baseline). (Kitayama et al, 1996;. In the current study, for the ®rst time, patient cells containing the mutation were directly analysed in vitro.…”

“…The equivalent mutation in the murine c-Kit receptor (Asp814!Tyr) induces factor independence, tumorigenicity and mast cell differentiation when introduced into factordependent haematopoietic cell lines (Kitayama et al, 1996;. Transplantation of mice with bone marrow cells harbouring the Asp814!Tyr c-Kit mutation leads to the development of acute leukaemia, and transgenic mice expressing the mutation developed haematological malignancies (Kitayama et al, 1996). These results suggested a direct role for this mutation in the malignant transformation of haematopoietic cells.…”

Mutations of p53, c‐kit, K‐ras, and β‐Catenin Gene in Non‐Hodgkin's Lymphoma of Adrenal Gland

“…9) The development of acute leukemia or malignant lymphoma was also reported in transgenic mice expressing a KIT mutant (Asp816→ Val). 10) Recently, a relative high frequency of c-kit gene mutations in human nasal NK/T-cell lymphoma was reported. 11) The K-ras gene encodes a 21-kD ras protein, GTP-and GDP-binding protein, which plays a role in signal transduction through transmembrane signaling systems.…”