Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase.
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.
Kitayama
H
H
Second Department of Internal Medicine, Osaka University Medical School, Japan.
Tsujimura
T
T
Matsumura
I
I
Oritani
K
K
Ikeda
H
H
Ishikawa
J
J
Okabe
M
M
Suzuki
M
M
Yamamura
K
K
Matsuzawa
Y
Y
Kitamura
Y
Y
Kanakura
Y
Y
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004789:Enzyme Activation; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006098:Granulocytes / Q000166:cytology / Q000201:enzymology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics* / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011519:Proto-Oncogenes; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit