附加性梳样1基因突变在髓系肿瘤中的研究进展

Advances on the research of additional sex combs like 1 mutation in myeloid malignancies

基因表达的适当调控依赖于无数表观遗传调节因子之间特定蛋白质的相互作用,编码表观遗传调节因子的基因发生突变,往往会导致肿瘤发生及机体发育障碍。附加性梳样1(ASXL1)基因是一种表观遗传调控因子,在维持基因表达稳态中发挥重要作用。ASXL1突变常导致蛋白翻译过程提前结束,产生C端缺失的截短蛋白。随着基因测序技术不断发展,多种髓系肿瘤中已检测到ASXL1突变,如急性髓系白血病、骨髓增生异常综合征、骨髓增殖性肿瘤、慢性粒-单核细胞白血病等,且预示着较差的临床结局。目前认为突变ASXL1与BAP1、BRD4、Bmi1、Akt/mTOR、HHEX等其他靶点及信号轴相互作用可能促进髓系肿瘤的发展。本研究对ASXL1的结构与功能、突变的分子机制及其在髓系肿瘤中的研究进展进行综述。

Proper regulation of gene-expression relies on specific protein-protein interactions between a myriad of epigenetic regulators.Therefore,mutation of genes encoding epigenetic regulators often lead to tumorigenesis and developmental disorders.Additional sex combs like 1(ASXL1)is an epigenetic regulator that plays an important role in gene expression homeostasis.ASXL1 mutations often lead to an early end of the protein translation process,resulting in truncated proteins without C-terminal.With the development of gene sequencing,ASXL1 mutations have been detected in a variety of myeloid malignancies,such as acute myeloid leukemia,myelodysplasia syndrome,myeloproliferative neoplasm,chronic myelomonocytic leukemia,and predicts poor clinical outcomes.It is currently believed that the mutant ASXL1 interacts with some targets and signal axes such as BAP1,BRD4,Bmi1,Akt/mTOR,HHEX and so on,may promote the development of myeloid malignancies.This article reviews the structure and function of ASXL1,the molecular mechanism of its mutation and the advances of ASXL1-mutated myeloid malignancies.