Clustering of activating mutations in c-KIT's juxtamembrane coding region in canine mast cell neoplasms

被引:125
作者
Ma, YS
Longley, BJ
Wang, XM
Blount, JL
Langley, K
Caughey, GH
机构
[1] Columbia Univ Coll Phys & Surg, Dept Dermatol, Sect Dermatopathol, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
[3] Univ Calif San Francisco, Dept Med, San Francisco, CA USA
[4] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA USA
[5] Amgen, Thousand Oaks, CA USA
关键词
c-KIT; in situ; mastocytosis; receptor tyrosine kinase; stem cell factor;
D O I
10.1046/j.1523-1747.1999.00488.x
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
The proto-oncogene c-KIT encodes a growth factor receptor, KIT, with Ligand-dependent tyrosine kinase activity that is expressed by several cell types including mast cells. c-KIT juxtamembrane coding region mutations causing constitutive activation of KIT are capable of transforming cell lines and have been identified in a human mast cell line and in situ in human gastrointestinal stromal tumors, but have not been demonstrated in situ in neoplastic mast cells from any species. To determine whether c-KIT juxtamembrane mutations occur in the development of mast cell neoplasms, we examined canine mastocytomas, which are among the most common tumors of dogs and which often behave in a malignant fashion, unlike human solitary mastocytomas. Sequencing of c-KIT cDNA generated from tumor tissues removed from seven dogs revealed that three of the tumors contained a total of four mutations in an intracellular juxtamembrane coding region that is completely conserved among vertebrates. In addition, two mutations were found in three mast cell lines derived from two additional dogs. One mutation from one line matched that found in situ in one of the tumors. The second was found in two lines derived from one dog at different times, indicating that the mutation was present in situ in the animal. All five mutations cause high spontaneous tyrosine phosphorylation of KIT. Our study provides in situ evidence that activating c-KIT juxtamembrane mutations are present in, and may therefore contribute to, the pathogenesis of mast cell neoplasia. Our data also suggest an inhibitory role for the KIT juxtamembrane region in controlling the receptor kinase activity.
引用
收藏
页码:165 / 170
页数:6
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