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

doi:10.3969/j.issn.1674-8115.2024.10.011

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (10): 1287-1298.doi: 10.3969/j.issn.1674-8115.2024.10.011

• 综述 • 上一篇

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

方馨悦¹(), 石岚¹, 夏思易¹, 王佳璇¹, 吴英理²(), 何珂骏³()

^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

收稿日期:2024-04-30 接受日期:2024-06-04 出版日期:2024-10-28 发布日期:2024-10-28
通讯作者: 吴英理,何珂骏 E-mail:xinyue.fang@qq.com;wuyingli@shsmu.edu.cn;hekejun@hotmail.com
作者简介:方馨悦（2000—），女，本科生；电子信箱：xinyue.fang@qq.com。
基金资助:
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)

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

FANG Xinyue¹(), SHI Lan¹, XIA Siyi¹, WANG Jiaxuan¹, WU Yingli²(), HE Kejun³()

^1.Faculty of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
^2.Department of Pathophysiology, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China
^3.Pediatric Hematology and Oncology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

Received:2024-04-30 Accepted:2024-06-04 Online:2024-10-28 Published:2024-10-28
Contact: WU Yingli,HE Kejun E-mail:xinyue.fang@qq.com;wuyingli@shsmu.edu.cn;hekejun@hotmail.com
Supported by:
National Key Research and Development Program of China(2022YFC2705003);Shanghai Jiao Tong University School of Medicine Undergraduate Innovation Training(1521Y493)

摘要/Abstract

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。

关键词: MLL基因重排白血病, Menin, 靶向治疗, Menin-MLL抑制剂

Abstract:

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.

Key words: MLL-rearranged leukemia, Menin, targeted therapy, Menin-MLL inhibitor

中图分类号:

R733.71

方馨悦, 石岚, 夏思易, 王佳璇, 吴英理, 何珂骏. 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[J]. 上海交通大学学报（医学版）, 2024, 44(10): 1287-1298.

FANG Xinyue, SHI Lan, XIA Siyi, WANG Jiaxuan, WU Yingli, HE Kejun. Research progress in Menin-MLL interaction and its inhibitors in MLL-rearranged leukemia[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(10): 1287-1298.

图/表 5

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Drug	Reference	Phase	Designment	Status/ Results
Revumenib (SNDX-5613)	NCT04065399 (AUGMENT-101)	Ⅰ	AML, ALL	n=94, discontinuation: 6.4%
	NCT04065399 (AUGMENT-101)	Ⅱ	r/r AML with MLL-r, r/r ALL with MLL-r, r/r AML with mNPM1	n=57, ORR=63.2%, CRc=43.9% (r/r AML with MLL-r and r/r ALL with MLL-r); n=13, ORR=46.2%, CRc=38.5% (pediatric r/r AML with MLL-r and r/r ALL with MLL-r)
	NCT05360160 (SAVE)	Ⅰ/Ⅱ	r/r AML with MLL-r/mNPM1/NUP98-r: ASTX727/venetoclax	n=9, ORR=100%, CRc=78%
	NCT05326516 (AUGMENT-102)	Ⅰ	r/r AML, ALL with MLL-r/mNPM1/NUP98-r: Chemo Regimen 1, Chemo Regimen 2	n=15, CRc=33% (Chemo Regimen 2)
	NCT03013998 (BEAT-AML)	Ⅰ	AML with MLL-r/mNPM1, age≥60 years: venetoclax/azacitidine	n=13, CRc=100%
	ACTRN12621000439842	Ⅰ/Ⅱ	MRD⁺AML with MLL-r/mNPM1	Recruiting, unavailable
	NCT05886049	Ⅰ	AML with MLL-r/mNPM1: 7+3 chemo	Recruiting, unavailable
	NCT06222580	Ⅰ	r/r AML with MLL-r/mNPM1 FLT3 co-mutation: gilteritinib	Recruiting, unavailable
	NCT06226571	Ⅰ	AML with MLL-r/mNPM1/NUP98-r: intensive chemotherapy	Recruiting, unavailable
	NCT05761171	Ⅱ	Pediatric r/r ALL, AML with MLL-r: fludarabine	Recruiting, unavailable
	NCT06177067	Ⅰ	Pediatric or young adult r/r AML with MLL-r/mNPM1/NUP98-r: venetoclax/azacitidine	Recruiting, unavailable
	NCT05918913	Expanded	r/r acute leukemia with genetic alterations associated with HOXA overexpression	Recruiting, unavailable
Ziftomenib (KO-539)	NCT04067336 (KOMET-001)	Ⅰ	r/r AML with MLL-r/mNPM1	n=20, ORR=45%, CRc=40%
	NCT04067336 (KOMET-001)	Ⅱ	r/r AML with mNPM1	n=20, ORR=45%, CRc=40%
	NCT05735184 (KOMET-007)	Ⅰ	AMLwith MLL-r/mNPM1: venetoclax & azacitidin, venetoclax, 7+3 chemo	n=9, ORR=78%, CRc=67% (venetoclax & azacitidin); n=5, CRc=100% (7+3 chemo)
	NCT06001788 (KOMET-008)	Ⅰ	r/r AML with MLL-r/mNPM1: FLAG-IDA, LD-AraC + gilteritinib (FLT3 co-mutation)	Recruiting, unavailable
	NCT05848687	Ⅰ/Ⅱ	Infant ALL	Recruiting, unavailable
	NCT05738538	Expanded	ALL with appropriate mutations, or AML with mNPM1	Recruiting, unavailable
Icovamenib (BMF-219)	NCT05153330 (COVALENT-101)	Ⅰ	r/r AML, ALL, DLBCL, MM, CLL	n=5, CRc=40% (r/r AML)
Emilumenib (DS-1594)	NCT04752163	Ⅰ	r/r AML, ALL	Completed, unavailable
Emilumenib (DS-1594)	NCT04752163	Ⅱ	r/r AML with MLL-r/mNPM1: venetoclax & azacitidine. r/r ALL with MLL-r: mini-HCVD	Completed, unavailable
DSP-5336	NCT04988555	Ⅰ	r/r AML, ALL	n=6, CRc=33.3%
DSP-5336	NCT04988555	Ⅱ	r/r AML with MLLr, an r/r AML with mNPM1	n=6, CRc=33.3%
JNJ-75276617	NCT04811560	Ⅰ/Ⅱ	r/r AML, ALL with MLL-r/mNPM1	n=41, CRc=29.2%
JNJ-75276617	NCT05453903	Ⅰ	AML with MLL-r/mNPM1: venetoclax, azacitidine or 7+3 chemo	Recruiting, unavailable
BN-104	NCT06052813	Ⅰ/Ⅱ	r/r AML, ALL	Recruiting, unavailable

Drug	Reference	Phase	Designment	Status/ Results
Revumenib (SNDX-5613)	NCT04065399 (AUGMENT-101)	Ⅰ	AML, ALL	n=94, discontinuation: 6.4%
	NCT04065399 (AUGMENT-101)	Ⅱ	r/r AML with MLL-r, r/r ALL with MLL-r, r/r AML with mNPM1	n=57, ORR=63.2%, CRc=43.9% (r/r AML with MLL-r and r/r ALL with MLL-r); n=13, ORR=46.2%, CRc=38.5% (pediatric r/r AML with MLL-r and r/r ALL with MLL-r)
	NCT05360160 (SAVE)	Ⅰ/Ⅱ	r/r AML with MLL-r/mNPM1/NUP98-r: ASTX727/venetoclax	n=9, ORR=100%, CRc=78%
	NCT05326516 (AUGMENT-102)	Ⅰ	r/r AML, ALL with MLL-r/mNPM1/NUP98-r: Chemo Regimen 1, Chemo Regimen 2	n=15, CRc=33% (Chemo Regimen 2)
	NCT03013998 (BEAT-AML)	Ⅰ	AML with MLL-r/mNPM1, age≥60 years: venetoclax/azacitidine	n=13, CRc=100%
	ACTRN12621000439842	Ⅰ/Ⅱ	MRD⁺AML with MLL-r/mNPM1	Recruiting, unavailable
	NCT05886049	Ⅰ	AML with MLL-r/mNPM1: 7+3 chemo	Recruiting, unavailable
	NCT06222580	Ⅰ	r/r AML with MLL-r/mNPM1 FLT3 co-mutation: gilteritinib	Recruiting, unavailable
	NCT06226571	Ⅰ	AML with MLL-r/mNPM1/NUP98-r: intensive chemotherapy	Recruiting, unavailable
	NCT05761171	Ⅱ	Pediatric r/r ALL, AML with MLL-r: fludarabine	Recruiting, unavailable
	NCT06177067	Ⅰ	Pediatric or young adult r/r AML with MLL-r/mNPM1/NUP98-r: venetoclax/azacitidine	Recruiting, unavailable
	NCT05918913	Expanded	r/r acute leukemia with genetic alterations associated with HOXA overexpression	Recruiting, unavailable
Ziftomenib (KO-539)	NCT04067336 (KOMET-001)	Ⅰ	r/r AML with MLL-r/mNPM1	n=20, ORR=45%, CRc=40%
	NCT04067336 (KOMET-001)	Ⅱ	r/r AML with mNPM1	n=20, ORR=45%, CRc=40%
	NCT05735184 (KOMET-007)	Ⅰ	AMLwith MLL-r/mNPM1: venetoclax & azacitidin, venetoclax, 7+3 chemo	n=9, ORR=78%, CRc=67% (venetoclax & azacitidin); n=5, CRc=100% (7+3 chemo)
	NCT06001788 (KOMET-008)	Ⅰ	r/r AML with MLL-r/mNPM1: FLAG-IDA, LD-AraC + gilteritinib (FLT3 co-mutation)	Recruiting, unavailable
	NCT05848687	Ⅰ/Ⅱ	Infant ALL	Recruiting, unavailable
	NCT05738538	Expanded	ALL with appropriate mutations, or AML with mNPM1	Recruiting, unavailable
Icovamenib (BMF-219)	NCT05153330 (COVALENT-101)	Ⅰ	r/r AML, ALL, DLBCL, MM, CLL	n=5, CRc=40% (r/r AML)
Emilumenib (DS-1594)	NCT04752163	Ⅰ	r/r AML, ALL	Completed, unavailable
Emilumenib (DS-1594)	NCT04752163	Ⅱ	r/r AML with MLL-r/mNPM1: venetoclax & azacitidine. r/r ALL with MLL-r: mini-HCVD	Completed, unavailable
DSP-5336	NCT04988555	Ⅰ	r/r AML, ALL	n=6, CRc=33.3%
DSP-5336	NCT04988555	Ⅱ	r/r AML with MLLr, an r/r AML with mNPM1	n=6, CRc=33.3%
JNJ-75276617	NCT04811560	Ⅰ/Ⅱ	r/r AML, ALL with MLL-r/mNPM1	n=41, CRc=29.2%
JNJ-75276617	NCT05453903	Ⅰ	AML with MLL-r/mNPM1: venetoclax, azacitidine or 7+3 chemo	Recruiting, unavailable
BN-104	NCT06052813	Ⅰ/Ⅱ	r/r AML, ALL	Recruiting, unavailable

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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

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