NPM1突变及H3K79甲基化的研究进展  

The research progress of NPM1 mutation and H3K79 metheylation

作　　者：赵晨[1] 颜晓菁[1] Zhao Chen;Yan Xiaojing(The First Hospital of China Medical University,Liaoning Shenyang 110000,China.)

机构地区：[1]中国医科大学附属第一医院,辽宁沈阳110000

出　　处：《现代肿瘤医学》2018年第13期2129-2133,共5页Journal of Modern Oncology

基　　金：霍英东教育基金会第十四届高等院校青年教师基金基础性研究课题(编号:141031);新世纪优秀人才支持计划(编号:NCET-13-1037)

摘　　要：白血病是一种常见的血液系统恶性肿瘤,其中急性髓系白血病(acute myeloid leukemia,AML)约占所有白血病的59%,其发病机理尚不十分清楚,现认为多种因素在多个层面、多个阶段的相互作用导致白血病的发生。NPM1蛋白可以穿梭于胞浆与胞核之间,并主要定位于细胞核内,与多种蛋白结合。NPM1突变在急性髓系白血病中占25～30%,产生的突变的NPM1蛋白因缺乏核定位肽段而滞留于细胞浆,对细胞核的稳定性以及某些癌基因的表达产生负面影响。在含有NPM1基因突变的AML中,约70%的病人同时含有DNA甲基化调节基因的突变(DNMT3A、IDH1、IDH2、TET2等),并且已知表观遗传学的异常可以直接破坏核稳定性,上调某些白血病相关基因的高表达。NPM1突变基因的白血病细胞具有特殊的基因表达特征,如HOX家族基因、MEIS1基因在突变系统中显著高表达,这些基因不仅是引发白血病的关键调节子,而且是MLL融合蛋白的下游靶点。在携带有MLL融合蛋白的AML中,MLL的融合伴侣可以募集DOT1L,对MLL靶点基因上的H3K79位点进行甲基化,造成这些基因过度活化。同MLL基因的异常相比,NPM1突变保持着相似的转录特点,然而NPM1突变是否能够影响组蛋白H3K79甲基化的变化还不是很清楚。本综述着重探讨NPM1突变与H3K79甲基化的关系,以及H3K79甲基化转移酶DOT1L抑制剂对NPM1突变的AML的作用,从而为白血病发病寻求新的分子机制和治疗策略。Leukenfia is a comnlon hemotology malignant tumor in recent years, in which acute myeliod leukenfia ac- counts for about 59%. However its pathogenesis remains unclear, and now it is believed that the interaction of multiple factors at multiple stages and nmltiple levels leads to the occurrence of leukenfia. NPM1 protein can shuttle between cytoplasm and nucleus, but mainly located in neucleus binding to various proteins. In adult AML, NPM1 mutation （NPMc ＋ ） is one of the most comnlon genetic lesions,accounting for approximately 25% -30% , and nmtated NPM1 remains in cytoplasm, therefor produces a negative impact on the stability- of nucleus and the express of some onco- genes. As we know about 70% NPM1 mutated AML has the mutation of DNA metheylation genes,such as DNMT3A, IDH1, IDH2 ,TET2, and the abnormal of epigenetics also can destroy the stability- of nucleus directly, then upregulate the expression of some related genes. HOX and MEIS1 genes,which are closely associated with leukemogenesis,arehighly expressed and regarded to be the feature of AML with NPMe ＋. In the meanwhile,these genes,especially HOX and MEISI, are the downstream regulator of MLL fusion oneoprotein that is mutually exclusive to NPMe ＋ in AML. MLL fusion genes can recruit DOT1L to metheylate H3K79 site, so that these genes can overactive. NPM1 has similar transcribe features with MLL fusion oneoproteins, however NPM1 nmtation whether can effect H3K79 metheylation does not know. This report emphasizes on the relationship between NPM1 nmtation and H3K79 methylation and DOT1 L inhibitorg function in NPM1 nmtated AML, consequently find a new treatment and molecular meehanisnl for leukemia.

关 键 词：NPM1基因突变 H3K79甲基化 AML MLL DOT1L 

分 类 号：R733.41[医药卫生—肿瘤]