Treatment of acute leukemia is gradually moving away from a "one-size-fits-all" approach, as scientific and clinical advances expand the arsenal of available targeted therapies. One of the recent additions are the menin inhibitors; oral, selective, small molecules that disrupt the interaction between the chromatin adapter menin, and an epigenetic regulator, the Lysine Methyltransferase 2A (KMT2A) complex. Two susceptible leukemia subtypes have been identified: 1) Acute Myeloid Leukemia (AML) with a mutation in Nucleophosmin 1 (NPM1), and 2) any acute leukemia, myeloid or lymphoid, with a translocation resulting in the rearrangement of KMT2A. These leukemias share a distinct genetic expression, maintained by the KMT2A-menin interaction. Together they account for approximately 40% of patients with AML, and 10% of patients with Acute Lymphoblastic Leukemia (ALL). This review follows the journey of revumenib, as a representative of menin inhibitors, from bench to bedside. It will focus on the pathophysiology of leukemias sensitive to menin inhibition, delineation of how this understanding led to targeted drug development, and data from clinical trials. The important discovery of resistance mechanisms will also be explored, as well as future directions in using menin inhibitors for treating leukemia.

中文翻译：

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Revumenib 用于急性白血病患者：一种分化治疗的新工具。


随着科学和临床进步扩大了可用靶向治疗的武器库，急性白血病的治疗正逐渐摆脱“一刀切”的方法。最近添加的药物之一是 menin 抑制剂;口服、选择性、小分子，破坏染色质衔接蛋白 menin 与表观遗传调节因子赖氨酸甲基转移酶 2A （KMT2A） 复合物之间的相互作用。已经确定了两种易感的白血病亚型：1） 核磷蛋白 1 （NPM1） 突变的急性髓性白血病 （AML），以及 2） 任何急性白血病，髓系或淋巴系，易位导致 KMT2A 重排。这些白血病具有独特的基因表达，由 KMT2A-menin 相互作用维持。他们合计约占 AML 患者的 40% 和急性淋巴细胞白血病 （ALL） 患者的 10%。本综述跟踪了 revumenib 作为 menin 抑制剂的代表，从实验室到床边的旅程。它将侧重于对 menin 抑制敏感的白血病的病理生理学，描述这种理解如何导致靶向药物开发，以及临床试验数据。还将探讨耐药机制的重要发现，以及使用 menin 抑制剂治疗白血病的未来方向。