Menin (MEN1) is a well-recognized powerful tumor promoter in acute leukemias (AL) with KMT2A rearrangements (KMT2Ar, also known as MLL) and mutant nucleophosmin 1 (NPM1m) acute myeloid leukemia (AML). MEN1 is essential for sustaining leukemic transformation due to its interaction with wild-type KMT2A and KMT2A fusion proteins, leading to the dysregulation of KMT2A target genes. MEN1 inhibitors (MIs), such as revumenib, ziftomenib, and other active small molecules, represent a promising new class of therapies currently under clinical development. By disrupting the MEN1-KMT2Ar complex, a group of proteins involved in chromatin remodeling, MIs induce apoptosis and differentiation AL expressing KMT2Ar or NPM1m AML. Phase I and II clinical trials have evaluated MIs as standalone treatments and combined them with other synergistic drugs, yielding promising results. These trials have demonstrated notable response rates with manageable toxicities. Among MIs, ziftomenib received orphan drug and breakthrough therapy designations from the European Medicines Agency in January 2024 and the Food and Drug Administration (FDA) in April 2024, respectively, for treating R/R patients with NPM1m AML. Additionally, in November 2024, the FDA approved revumenib for treating R/R patients with KMT2Ar-AL. This review focuses on the pathophysiology of MI-sensitive AL, primarily AML. It illustrates data from clinical trials and discusses the emergence of resistance mechanisms. In addition, we outline future directions for the use of MIs and emphasize the need for further research to fully realize the potential of these novel compounds, especially in the context of specific genetic subtypes of challenging AL.
Menin（MEN1）是公认的急性白血病（AL）中强有力的肿瘤促进因子，尤其见于KMT2A重排（KMT2Ar，亦称为MLL）和突变型核磷蛋白1（NPM1m）急性髓系白血病（AML）。MEN1通过与野生型KMT2A及KMT2A融合蛋白相互作用，导致KMT2A靶基因失调，对维持白血病转化至关重要。MEN1抑制剂（MIs），如revumenib、ziftomenib及其他活性小分子，代表了一类目前处于临床开发阶段、前景广阔的新型疗法。通过破坏参与染色质重塑的蛋白质复合体MEN1-KMT2Ar，MIs能诱导表达KMT2Ar或NPM1m的AML细胞发生凋亡与分化。I期和II期临床试验已评估了MIs作为单药治疗或与其他协同药物联合使用的效果，并取得了令人鼓舞的结果。这些试验显示MIs具有显著的反应率且毒性可控。在MIs中，ziftomenib分别于2024年1月获得欧洲药品管理局、2024年4月获得美国食品药品监督管理局（FDA）授予的孤儿药资格和突破性疗法认定，用于治疗NPM1m AML的复发/难治性患者。此外，2024年11月，FDA批准revumenib用于治疗KMT2Ar-AL的复发/难治性患者。本综述聚焦于对MI敏感的AL（主要为AML）的病理生理学，展示临床试验数据并讨论耐药机制的出现。同时，我们概述了MIs应用的未来方向，并强调需要进一步研究以充分实现这些新型化合物的潜力，特别是在具有挑战性的AL特定遗传亚型背景下。
肿瘤(癌症)患者之家