患有NPM1基因突变相关的急性髓系白血病（AML）的患者，尤其是60岁以上的患者，没有可行的靶向治疗选择。在本研究中，我们鉴定了HEN-463，一种特异性靶向AML携带该基因突变的倍半萜内酯衍生物。该化合物通过共价结合核糖体生物发生相关蛋白LAS1的C264位点，从而抑制LAS1-NOL9的相互作用，将LAS1转位到细胞质，从而抑制28S rRNA的成熟。这对NPM1-MDM2-p53通路产生深远的影响，最终导致p53的稳定。将该治疗与XPO1抑制剂Selinexor（Sel）联合使用可以理想地保留核内稳定的p53，显著增强HEN-463的疗效，并解决Sel的耐药性。年龄超过60岁的AML患者携带NPM1突变通常具有异常升高的LAS1水平，这对他们的预后产生重要影响。在NPM1突变的AML细胞中，减少LAS1表达促进增殖抑制、凋亡、细胞分化和细胞周期停滞。这提示它可能是这种血液癌症的治疗靶点，特别是60岁以上的患者。版权所有2013年作者。由Elsevier Ltd.出版。保留所有权利。

Patients with NPM1 gene mutation-associated acute myeloid leukemia (AML), particularly those over the age of 60, have no viable targeted therapeutic choices. In this study, we identified HEN-463, a sesquiterpene lactone derivative specific targets AML with this gene mutation. This compound inhibits the interaction of LAS1-NOL9 by covalently binding to the C264 site of the ribosomal biogenesis-related protein LAS1, which translocates the LAS1 to the cytoplasm, thereby inhibiting the maturation of 28 S rRNA. This has a profound effect on the NPM1-MDM2-p53 pathway and ultimately results in the stabilization of p53. Combining this treatment with the XPO1 inhibitor Selinexor (Sel) can ideally preserve the stabilized p53 in the nucleus, considerably enhancing the efficacy of HEN-463 and addressing Sel's drug resistance. Patients with AML over the age of 60 who possess the NPM1 mutation have an unusually elevated level of LAS1, which has a significant impact on their prognosis. In NPM1-mutant AML cells, decreased LAS1 expression promotes proliferation inhibition, apoptosis, cell differentiation, and cell cycle arrest. This suggests that it may be a therapeutic target for this kind of blood cancer, especially in patients over the age of 60.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.