小细胞肺癌（SCLC）广泛存在四种分子亚型：ASCL1，NEUROD1，POU2F3和Inflammatory。最初，人们认为SCLC的亚型是互斥的，但最近的证据显示存在亚型之间的肿瘤内亚型异质性和可塑性。在这里，我们使用基于CRISPR的自发性SCLC基因工程小鼠模型来研究KDM6A/UTX失活的后果，我们发现KDM6A失活促使ASCL1向NEUROD1的可塑性变化，导致SCLC肿瘤同时表达ASCL1和NEUROD1。从机制上讲，KDM6A通常维持有利于ASCL1亚型的活性染色质状态，其缺失会降低神经内分泌基因的增强子上的H3K4me1并增加H3K27me3，导致细胞状态呈现出ASCL1转变为NEUROD1亚型的倾向。这项工作确定了KDM6A作为一个表观遗传调节因子，控制ASCL1到NEUROD1亚型的可塑性，并提供了一个自发性SCLC基因工程小鼠模型，用于模拟ASCL1和NEUROD1亚型的异质性和可塑性，这在人类SCLC中占35-40％。© 2023. 作者，向Springer Nature Limited独家授权。

Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.