Influence of various types of receptor tyrosine kinase gene mutations in pathogenesis of GISTs

激酶结构域II纯合突变敲入小鼠肥大细胞培养的永生化肥大细胞系激活的信号转导系统与敲入小鼠培养的激酶结构域II纯合突变敲入小鼠肥大细胞激活的信号转导系统不同。永生化肥大细胞系在c-kit基因中有一个额外的突变。伊马替尼和尼洛替尼可有效抑制家族性gist中新发现的近膜结构域种系c-kit基因功能获得突变的激活。我们还发现，与常规的细胞外结构域c-kit基因突变相比，伊马替尼和尼洛替尼有效地抑制了散发性gist中新发现的细胞外结构域c-kit基因突变的激活。

Signal transduction system activated in immortalized mast cell line which is derived from cultured mast cells of knock-in mice with germline homozygous mutation at kinase domain II was different from that in cultured mast cells of knock-in mice with germline homozygous mutation. The immortalized mast cell line had an additional mutation in the c-kit gene.Activation of newly found juxtamembrane domain germline c-kit gene gain-of-function mutation in familial GISTs was effectively inhibited by imatinib and nilotinib. We also found that activation of newly found extracellular domain c-kit gene mutation in sporadic GISTs is effectively inhibited by imatinib and nilotinib, compared to that of conventional extracellular domain c-kit gene mutation.