Pathological analysis of GIST using transgenic or knock-in-mouse

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First, we tried to generate transgenic mice possessing c-kit gene mutation which was seen in patients with familial and multiple GISTs (gastrointestinal stromal tumors). Two types of transgenic mice was gained; one had juxtamembrane domain mutation and the other had tyrosine kinase n domain mutation. However, these mice showed neither hyperplasia of interstitial cells of Cajal (IGCs) nor multiple GISTs. We are generating knock-in-mouse as a more physiological model of human familial GISTs. The knock-in-mouse has c-kit gene mutation at tyrosine kinase II domain. We will investigate the knock-in-mouse in near future.During the above process, we examined the clonality of diffuse proliferation of ICCs in familial GIST patients. The proliferate lesion showed polyclonal nature while each GIST demonstrated to be monoclonal. We also showed that KIT activation by exon 17 mutation was not effectively inhibited by a selective tyrosine kinase inhibitor, Imatinib. The downstream molecules of KIT signal transduction were not also fully inhibited by Imatinib.We investigated the cause of GISTs without c-kit gene mutation. Approximately half of GISTs without c-kit gene mutation had PDGFR alpha gene mutation. Two types of PDGFR alpha gene mutation were seen, and the juxtamembrane domain mutation was effectively inhibited by Imatinib but the tyrosine kinase n domain mutation was not We demonstrated that regrowth of GISTs during the Imatinib treatment (development of resistant clone) was caused by an additional c-kit gene mutation to original c-kit gene mutatioa Moreover, we showed that GISTs from neuroflbromatosis type1 patients did not have any c-kit gene mutation.