FBXW7在成人T细胞性急性淋巴细胞白血病中的突变研究  

Mutations of FBXW7 in Adult T-Cell Acute Lymphocytic Leukemia

作　　者：郭星[1] 张闰[1] 葛峥[1] 许景艳[2] 李敏[1] 乔纯[1] 仇海荣[1] 李建勇[1] 

机构地区：[1]南京医科大学第一附属医院,江苏省人民医院血液科,江苏南京210029 [2]南京大学医学院附属医院,南京市鼓楼医院血液科,江苏南京210008

出　　处：《中国实验血液学杂志》2015年第3期612-618,共7页Journal of Experimental Hematology

基　　金：国家自然科学基金面上项目(30973376,81270613);江苏省医学重点人才(RC2011077);中国博士后科学基金特别资助(201003598);中国博士后科学基金(20090461134);教育部"留学回国人员科研启动基金"(第39批);江苏省"六大人才高峰"资助(2010-WS-024);南京市留学回国人员科技活动项目择优资助(2009)

摘　　要：背景:F-Box和WD40蛋白7(F-Box and WD40 domain protein 7,FBXW7)是E3泛素连接酶复合物的组份,控制NOTCH1,c-MYC和Cyclin E等多种蛋白的降解。目的:研究成人T细胞性急性淋巴细胞白血病(T-ALL)中FBXW7基因突变。方法:通过对54例成人T-ALL患者FBXW7外显子5-12进行扩增、克隆和测序,分析FBXW7突变的发生率、突变位点和类型、与NOTCH1突变的相关性及其临床预后意义。结果:本组成人T-ALL中FBXW7突变率11.1%,共发现4种点突变(R465H,R465L,R479P和R505C)和1个插入/缺失突变,FBXW7突变全部位于WD40结构域。研究还发现,FBXW7突变患者中83.3%同时存在NOTCH1突变,与FBXW7突变并存的NOTCH1突变均发生于HD结构域,包括点突变(L1574P,L1596H和L1600P),和缺失/插入突变。此外,研究还显示,FBXW7单独突变组患者的总生存时间比无突变组延长(P=0.049)。结论:FBXW7突变可能在NOTCH1介导的TALL发病机制有重要作用。Backgroud：F-Box and WD40 domain containing protein 7 gene （FBXW7） is part of the E3 ubiquitin ligase complex that controls the turnover of various proteins including NOTCH1, c-MYC and Cyclin E. Objective： To investigate the mutations of FBXW7 gene in adult T-cell acute lymphoblastic leukemia （T-ALL）. Methods： Exon 5 - 12 of FBXW7 were amplified, cloned and sequenced in 54 adult T-ALL patients; the frequency, position and types of FBXW7 mutation were analyzed; the co-existing of mutations with NOTCH1 and their relevant prognostic significance were explored as well. Results： FBXW7 mutations were identified in 11.1% of adult T-ALL patients. A total of 4 types of point mutations （R465H, R465L, R479P and R505C）and 1 deletion/insertion mutation were observed, and all of them located in WD40 domain of FBXW7. In addition, co-existing mutations with NOTCH1 were identified in 83.3 % of patients with FBXW7 mutation. Notably, the co-existed NOTCH1 mutations, including 3 point mutations （L1574P, L1596H and L1600P） and 2 deletion/insertion mutations located in HD domain. Furthermore, patients with FBXW7 mutation only had significantly longer overall survival compared with those without mutation （P = 0. 049 ）. Conclusion： FBXW7 mutations may play an important role in NOTCH1 mediated pathogenesis in T-ALL.

关 键 词：FBXW7 NOTCH1 成人 T细胞性急性淋巴细胞白血病 

分 类 号：R733.71[医药卫生—肿瘤]