Menin-MLL蛋白相互作用及相关抑制剂在MLL基因重排白血病中应用的研究进展  

Research progress in Menin-MLL interaction and its inhibitors in MLL-rearranged leukemia

作　　者：方馨悦 石岚 夏思易 王佳璇 吴英理[2] 何珂骏[3] FANG Xinyue;SHI Lan;XIA Siyi;WANG Jiaxuan;WU Yingli;HE Kejun(Faculty of Clinical Medicine,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Department of Pathophysiology,Shanghai Jiao Tong University College of Basic Medical Sciences,Shanghai 200025,China;Pediatric Hematology and Oncology,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China)

机构地区：[1]上海交通大学医学院临床医学院,上海200025 [2]上海交通大学基础医学院病理生理学系,上海200025 [3]上海交通大学医学院附属新华医院儿血液肿瘤科,上海200092

出　　处：《上海交通大学学报（医学版）》2024年第10期1287-1298,共12页Journal of Shanghai Jiao tong University:Medical Science

基　　金：国家重点研发计划重点专项(2022YFC270500);上海交通大学医学院大学生创新训练计划项目(1521Y493)。

摘　　要：混合谱系白血病(mixed lineage leukemia,MLL)基因重排(MLL-rearranged,MLL-r)引起的急性白血病亚型侵袭性高且预后不良,缺少特异性治疗手段。MLL蛋白具有组蛋白甲基转移酶活性,在胚胎发育和正常造血中必不可少,可通过功能结构域与多种蛋白质相互作用,形成大分子复合体,并通过表观修饰调节下游靶基因的表达。MLL-r转录形成MLL融合蛋白(MLL fusion protein,MLL-FP),其中MLL蛋白的C端被融合伙伴蛋白所取代。现已发现超过100种融合伙伴蛋白。分子机制研究发现,Menin蛋白是MLL-FP致白血病必不可少的辅助因子,通过与MLL-N端特定区域相互作用形成关键致病复合体,导致特定靶基因的异常表达。这为Menin-MLL相互作用抑制剂的开发提供了理论依据。截至目前,多种小分子化合物被发现能抑制Menin-MLL相互作用,包括噻吩嘧啶类、哌啶类、嘧啶类和大环拟肽类。至少7种以此为原型开发的药物进入临床试验,部分已在安全性、耐受性和疗效方面取得乐观的初步数据。该文从MLL蛋白的结构功能、MLL-r导致白血病的机制出发,对Menin-MLL蛋白相互作用抑制剂在MLL-r白血病中应用的研究进展进行综述。Acute leukemias caused by mixed lineage leukemia(MLL)gene rearrangements(MLL-r)are characterized by high invasiveness and a poor prognosis,with few specific treatment options available.MLL protein is essential in embryonic development and hematopoiesis.It exhibits histone methyltransferase activity and can interact with various proteins through its functional domains,thus regulating downstream target gene expression through epigenetic modifications.MLL-r leads to the formation of MLL fusion proteins(MLL-FPs),in which the C-terminal is replaced by fusion partner proteins;over 100 such partner proteins have been identified to date.In numerous studies of the molecular mechanism,Menin serves as an important cofacter in the leukemogenesis of MLL-FPs and participates in forming the key complex when interacting with the N terminal of MLL protein,resulting in the disregulation of certain targeted genes,which makes the development of Menin-MLL inhibitors theoretically possible.To date,several small molecules have been identified that inhibit Menin-MLL interaction,including thienopyrimidine derivatives,piperidine derivatives,pyrimidine derivatives,and macrocyclic mimic peptides.Based on these prototypes,at least seven drugs are currently undergoing clinical evaluation,with some promising preliminary data regarding safety,tolerability,and efficacy.This review summarizes the structure and function of MLL,the mechanism of the occurrence of MLL-r leukemia,and current Menin-MLL inhibitors tested in MLL-r leukemia.

关 键 词：MLL基因重排白血病 MENIN 靶向治疗 Menin-MLL抑制剂 

分 类 号：R733.71[医药卫生—肿瘤]