CLAPP, D. WADE,克拉普D 维德,克拉普D 維德,INGRAM, DAVID,因格拉姆 大卫,因格拉姆 大衛,YANG, FENG-CHUN,杨逢春,楊逢春
申请号：
TW098121297
公开号：
TWI508728B
申请日:
2009.06.25
申请国别(地区):
TW
年份:
2015
代理人:
摘要：
Germline mutations in the NF1 tumor suppressor gene cause Von Recklinghausen’s neurofibromatosis type 1 (NF1), a common genetic disorder of the nervous system characterized by plexiform neurofibroma development. Using adoptive transfer of hematopoietic cells, we establish that NF1 heterozygosity of bone marrow derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell nullizygosity. Further, genetic or pharmacologic attenuation of the c-kit signaling pathway in hematopoietic cells greatly diminishes neurofibroma initiation and progression. These studies identify haploinsufficient hematopoietic cells and the c-kit receptor as therapeutic targets for preventing plexiform neurofibromas and implicate mast cells as critical mediators of tumor initiation. Administering therapeutically effective doses of a tyrosine kinase inhibitor such as the compound imatinib mesylate to a patient in need thereof to treat tumors in a human patient afflicted with plexiform neurofibroma.在NF1腫瘤抑制子基因中的生殖種系突變,引起范瑞克林浩森氏神經纖維瘤病(Von Recklinghausen’s neurofibromatosis)第1型(NF1),是一種常見的神經系統遺傳病症,其特徵在於叢狀神經纖維瘤發育。使用造血細胞的繼承性轉移,我們建立了骨髓衍生細胞在腫瘤微環境中的NF1異型接合性(heterozygosity),足以允許神經纖維瘤在神經鞘細胞零合性(nullizygosity)的情況下進行。而且,在造血細胞中c-Kit發送信號路徑的遺傳或藥理學衰減,大大地減少了神經纖維瘤的開始和進行。這些研究鑑認單倍不足(haploinsufficient)的造血細胞和c-Kit受體為預防叢狀神經纖維瘤之治療目標,並涉及肥大細胞為腫瘤開始的關鍵性介體。對需要其之患者投予治療有效劑量的酪胺酸激酶抑制劑,如化合物甲磺酸伊馬替尼(imatinib mesylate),以便在受叢狀神經纖維瘤所苦之人類患者中治療腫瘤。
