Germline mutations in theMEN1gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical role in lysine methyltransferase 2A (KMT2A)-gene-rearranged andNPM1-m acute leukemias, both associated with adverse outcomes with current standard therapies, especially in the relapsed/refractory setting. Disrupting the menin–KMT2A interaction affects the proleukemogenicHOX/MEIStranscription program. This disruption leads to the differentiation ofKMT2Ar andNPM1-m AML cells. Small molecular inhibitors of the menin–KMT2A interaction target the central cavity of MEN1 to inhibit the MEN1-KMT2A interaction and could target a similar transcriptional dependency in other leukemia subsets, broadening their therapeutic potential. These agents, both as monotherapies and in combination with synergistic drugs, are undergoing preclinical and clinical evaluation with promising early results. With the growing literature around menin inhibitors in AML, we discussed the biology of menin, its mechanism of action, its interacting partners in leukemia, possible inhibitors, their implications, synergistic drugs, and future therapeutic strategies in this review.
编码menin蛋白的MEN1基因种系突变可导致1型多发性内分泌腺瘤综合征。最新研究表明，抑制menin蛋白与其关键致癌蛋白配体的相互作用，是急性髓系白血病一种极具前景的治疗策略。Menin蛋白在赖氨酸甲基转移酶2A基因重排和NPM1突变型急性白血病中发挥关键作用，这两类白血病采用现有标准疗法（尤其在复发/难治情况下）预后均不佳。破坏menin-KMT2A相互作用可影响促白血病发生的HOX/MEIS转录程序，进而诱导KMT2A重排和NPM1突变型AML细胞分化。靶向menin-KMT2A相互作用的小分子抑制剂通过作用于MEN1蛋白中心空腔抑制其与KMT2A的结合，并可能靶向其他白血病亚型中类似的转录依赖性，从而拓展其治疗潜力。这类药物无论是单药治疗还是与协同药物联合应用，目前均处于临床前和临床评估阶段，并已显示出良好的早期疗效。随着menin抑制剂在AML领域的研究文献日益丰富，本综述系统探讨了menin蛋白的生物学特性、作用机制、在白血病中的相互作用配体、潜在抑制剂及其临床意义、协同药物以及未来治疗策略。
Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions
肿瘤(癌症)患者之家