Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.

[1]  J. Vanderwinden,et al.  Study of the interstitial cells of Cajal in infantile hypertrophic pyloric stenosis. , 1996, Gastroenterology.

[2]  C. Cortesini,et al.  Neuromuscular structures specific to the submucosal border of the human colonic circular muscle layer. , 1990, Canadian journal of physiology and pharmacology.

[3]  Y. Suzuki,et al.  Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Y. Kitamura,et al.  Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. , 1978, Blood.

[5]  Y. Matsuzawa,et al.  Substitution of an aspartic acid results in constitutive activation of c-kit receptor tyrosine kinase in a rat tumor mast cell line RBL-2H3. , 1995, International archives of allergy and immunology.

[6]  Y. Matsuzawa,et al.  Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation , 1994 .

[7]  H. Asada,et al.  Possible involvement of c-kit receptor and its ligand in increase of mast cells in neurofibroma tissues. , 1993, Archives of pathology & laboratory medicine.

[8]  E. Russell.  Hereditary anemias of the mouse: a review for geneticists. , 1979, Advances in genetics.

[9]  H. Kitayama,et al.  Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. , 1995, Blood.

[10]  Laura H. Tang,et al.  Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm , 1996, Nature Genetics.

[11]  J. Rumessen,et al.  Light- and electron microscopical studies of interstitial cells of Cajal and muscle cells at the submucosal border of human colon. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[12]  J. Rumessen,et al.  Interstitial cells of Cajal in human colon and in Hirschsprung's disease. , 1996, Gastroenterology.

[13]  L. Ashman,et al.  Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. , 1993, The Journal of clinical investigation.

[14]  S. Hirota,et al.  Expression of bone matrix protein messenger ribonucleic acids in human breast cancers. Possible involvement of osteopontin in development of calcifying foci. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[15]  S. Nishikawa,et al.  Requirement of c-kit for development of intestinal pacemaker system. , 1992, Development.

[16]  C. March,et al.  Identification of a ligand for the c-kit proto-oncogene , 1990, Cell.

[17]  M. Miettinen,et al.  Gastrointestinal stromal tumors--value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas. , 1995, The American journal of surgical pathology.

[18]  D. Housman,et al.  The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene , 1988, Cell.

[19]  Y. Matsuzawa,et al.  Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain. , 1996, Blood.

[20]  L. Sobin,et al.  CD34 immunoexpression in stromal tumours of the gastrointestinal tract and in mesenteric fibromatoses , 1994, Histopathology.

[21]  M. Seto,et al.  Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. , 1993, The American journal of pathology.

[22]  S. Hirota,et al.  Disturbed intestinal movement, bile reflux to the stomach, and deficiency of c-kit-expressing cells in Ws/Ws mutant rats. , 1995, Gastroenterology.

[23]  John Malysz,et al.  W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity , 1995, Nature.

[24]  John E. Murphy,et al.  A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family , 1986, Nature.