成人T细胞急性淋巴细胞白血病中FBXW7的突变

[Mutations of FBXW7 in Adult T-Cell Acute Lymphocytic Leukemia].

作者信息

Guo Xing, Zhang Run, Ge Zheng, Xu Jing-Yan, Li Min, Qiao Chun, Qiu Hai-Rong, Li Jian-Yong

机构信息

Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Provincial People Hospital, Nanjing 210029, Jiangsu Province, China.

Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Provincial People Hospital, Nanjing 210029, Jiangsu Province, China. E-mail:

出版信息

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2015 Jun;23(3):612-8. doi: 10.7534/j.issn.1009-2137.2015.03.002.

DOI:10.7534/j.issn.1009-2137.2015.03.002

PMID:26117003

Abstract

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.

摘要

背景

含F-Box和WD40结构域蛋白7基因（FBXW7）是E3泛素连接酶复合体的一部分，该复合体控制包括NOTCH1、c-MYC和细胞周期蛋白E在内的多种蛋白质的周转。

目的

研究成人T细胞急性淋巴细胞白血病（T-ALL）中FBXW7基因的突变情况。

方法

对54例成人T-ALL患者的FBXW7基因第5-12外显子进行扩增、克隆和测序；分析FBXW7突变的频率、位置和类型；探讨其与NOTCH1突变的共存情况及其相关预后意义。

结果

11.1%的成人T-ALL患者中检测到FBXW7突变。共观察到4种点突变（R465H、R465L、R479P和R505C）和1种缺失/插入突变，均位于FBXW7的WD40结构域。此外，83.3%的FBXW7突变患者中检测到与NOTCH1共存的突变。值得注意的是，共存的NOTCH1突变包括3种点突变（L1574P、L1596H和L1600P）和2种位于HD结构域的缺失/插入突变。此外，仅FBXW7突变的患者总生存期显著长于无突变患者（P=0.049）。