{"title":"Menin inhibitors in KMT2A-rearranged leukemia: Mechanistic insights, clinical trial progress, and potential of combination therapies","authors":"Xinyu Yang , Rui Huang","doi":"10.1016/j.leukres.2025.107924","DOIUrl":null,"url":null,"abstract":"<div><div>Leukemia driven by rearrangement of the Lysine Methyltransferase 2 A (KMT2A) gene, formerly known as mixed-lineage leukemia (MLL), is associated with poor prognosis due to the formation of oncogenic fusion proteins. Menin, a scaffold protein encoded by the MEN1 gene, plays a critical role in the pathogenesis of KMT2A-rearranged (KMT2A-r) leukemia. Targeting menin has emerged as a promising therapeutic strategy, leading to the development of several menin inhibitors, some of which have entered clinical trials. Notably, Revumenib has been approved for clinical use. However, resistance to menin inhibition is an increasing concern, necessitating alternative approaches. Combining menin inhibitors with other therapeutic strategies appears to enhance efficacy and mitigate resistance. This review summarizes recent advancements in menin inhibitor research for KMT2A-r leukemia, including mechanistic insights and clinical trial progress, while also exploring the potential of combination therapies. A deeper understanding of the mechanisms underlying menin inhibition and resistance is crucial for developing more effective treatments to improve patient outcomes.</div></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"157 ","pages":"Article 107924"},"PeriodicalIF":2.2000,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S014521262500284X","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Leukemia driven by rearrangement of the Lysine Methyltransferase 2 A (KMT2A) gene, formerly known as mixed-lineage leukemia (MLL), is associated with poor prognosis due to the formation of oncogenic fusion proteins. Menin, a scaffold protein encoded by the MEN1 gene, plays a critical role in the pathogenesis of KMT2A-rearranged (KMT2A-r) leukemia. Targeting menin has emerged as a promising therapeutic strategy, leading to the development of several menin inhibitors, some of which have entered clinical trials. Notably, Revumenib has been approved for clinical use. However, resistance to menin inhibition is an increasing concern, necessitating alternative approaches. Combining menin inhibitors with other therapeutic strategies appears to enhance efficacy and mitigate resistance. This review summarizes recent advancements in menin inhibitor research for KMT2A-r leukemia, including mechanistic insights and clinical trial progress, while also exploring the potential of combination therapies. A deeper understanding of the mechanisms underlying menin inhibition and resistance is crucial for developing more effective treatments to improve patient outcomes.
由赖氨酸甲基转移酶2 A (KMT2A)基因重排驱动的白血病,以前称为混合谱系白血病(MLL),由于形成致癌融合蛋白而与预后不良相关。Menin是一种由MEN1基因编码的支架蛋白,在kmt2a -重排(KMT2A-r)白血病的发病机制中起关键作用。靶向menin已成为一种有前景的治疗策略,导致几种menin抑制剂的开发,其中一些已进入临床试验。值得注意的是,Revumenib已被批准用于临床应用。然而,对menin抑制的耐药性是一个日益关注的问题,需要替代方法。将menin抑制剂与其他治疗策略联合使用似乎可以提高疗效并减轻耐药性。本文综述了近年来menin抑制剂治疗KMT2A-r白血病的研究进展,包括机制见解和临床试验进展,同时也探讨了联合治疗的潜力。更深入地了解menin抑制和耐药性的机制对于开发更有效的治疗方法以改善患者的预后至关重要。
期刊介绍:
Leukemia Research an international journal which brings comprehensive and current information to all health care professionals involved in basic and applied clinical research in hematological malignancies. The editors encourage the submission of articles relevant to hematological malignancies. The Journal scope includes reporting studies of cellular and molecular biology, genetics, immunology, epidemiology, clinical evaluation, and therapy of these diseases.