牛津大学施扬团队在研究中取得进展。他们研究出干扰LSD1和WNT重组转录以协同诱导AML分化。相关论文于2025年4月16日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该研究组证明了同时抑制组蛋白去甲基化酶LSD1 （LSD1i）和WNT途径拮抗剂GSK3激酶4 （GSK3i），可显著促进已建立的AML细胞系和原代人AML细胞的治疗性分化，并减轻肿瘤负担，显著延长患者来源的异种移植物同源性模型的生存期。从机制上讲，这种组合通过诱导转录因子如IRF7 （LSD1i）和共激活因子β-catenin （GSK3i）的表达，激活I型干扰素途径中的基因，并在STAT1等靶标上选择性共占据，从而促进分化，这是组合诱导分化所必需的。联合治疗也抑制典型的促癌WNT通路和细胞周期基因。对AML患者数据集的分析表明，联合诱导的转录特征与更好的预后之间存在相关性，突出了该策略的临床潜力。总的来说，这种组合策略重新连接转录程序以抑制干细胞并促进分化，这可能对AML和WNT驱动的非AML癌症具有重要的治疗意义。

据了解，分化受损是髓系恶性肿瘤的一个特征。使细胞能够绕过分化障碍的疗法，如全反式维甲酸（ATRA）和三氧化二砷（ATO），总体上治疗急性早幼粒细胞白血病，但“分化疗法”是否可用于急性髓性白血病（AML）及其他疾病的普遍治疗方法仍不完全清楚。

附：英文原文

Title: Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

Author: Hosseini, Amir, Dhall, Abhinav, Ikonen, Nemo, Sikora, Natalia, Nguyen, Sylvain, Shen, Yuqi, Amaral, Maria Luisa Jurgensen, Jiao, Alan, Wallner, Felice, Sergeev, Philipp, Lim, Yuhua, Yang, Yuanqin, Vick, Binje, Kawabata, Kimihito Cojin, Melnick, Ari, Vyas, Paresh, Ren, Bing, Jeremias, Irmela, Psaila, Bethan, Heckman, Caroline A., Blanco, M. Andrs, Shi, Yang

Issue&Volume: 2025-04-16

Abstract: Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether ‘differentiation therapy’ is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.

DOI: 10.1038/s41586-025-08915-1

Source: https://www.nature.com/articles/s41586-025-08915-1