ELP1相关音猬因子髓母细胞瘤的遗传学模型揭示MDM2可作为选择性治疗靶点，这一成果由美国圣裘德儿童研究医院Paul A. Northcott研究团队经过不懈努力而取得。这一研究成果于2025年5月15日发表在国际顶尖学术期刊《癌细胞》上。

伸长乙酰转移酶复合体亚单位1 （ELP1）的种系功能丧失（LOF）变异是儿童髓母细胞瘤（MB）中最普遍的易感遗传事件，占音猬因子 (SHH) 3亚型的约30%。种系ELP1缺陷引发SHH-MB发病机制尚不清楚。

在受影响的种系携带者中观察到的模拟Elp1 LOF杂合子（Elp1HET）的基因工程小鼠在小脑颗粒神经元祖细胞（GNPs）中表现出恶性前病变的标志性特征，包括DNA复制压力增加、基因组不稳定、细胞周期加速和分化停滞。携带体细胞Ptch1失活的Elp1HET GNPs原位移植产生p53信号受损的SHH-MB样肿瘤，为SHH-3亚型中Elp1相关的MB的排他性提供了合理的解释。临床前治疗Elp1突变患者来源的异种移植物与FDA批准的MDM2抑制剂重新激活p53依赖性细胞凋亡和延长生存期。他们的发现从功能上证实了ELP1缺乏在SHH-MB易感性中的作用，并提出了靶向MDM2的治疗方法作为合理的治疗选择。

附：英文原文

Title: Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target

Author: Shiekh Tanveer Ahmad, Yiran Li, Jesus Garcia-Lopez, Brian L. Gudenas, Jennifer Hadley, Leena Paul, Stephanie C. Wu, Alaa Refaat, Marija Kojic, Melissa Batts, Taha Soliman, Aaron Pitre, Frederik Arnsktter, Frederique Zindy, Alun Jones, Nathaniel R. Twarog, Anand Mayasundari, Brandon Bianski, Christopher Tinkle, Abbas Shirinifard, Laura Janke, Meifen Lu, Sara A. Lewis, Arzu Onar-Thomas, Stefan M. Pfister, Amar Gajjar, Suzanne J. Baker, Martine F. Roussel, Zoran Rankovic, Giles W. Robinson, Brent A. Orr, Brandon Wainwright, Anang A. Shelat, SebastianM. Waszak, Lena M. Kutscher, Hong Lin, Paul A. Northcott

Issue&Volume: 2025-05-15

Abstract: Germline loss-of-function (LOF) variants in Elongator acetyltransferase complex subunit 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ～30% of the Sonic hedgehog (SHH) 3 subtype. The mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of premalignancy in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yields SHH-MB-like tumors with compromised p53 signaling, providing a plausible explanation for the exclusivity of ELP1-associated MBs in the SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivates p53-dependent apoptosis and extends survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics targeting MDM2 as a rational treatment option.

DOI: 10.1016/j.ccell.2025.04.014

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00173-4