最近的全外显子研究发现，原发性纵隔B细胞淋巴瘤（PMBCL）及相关疾病中的表观遗传修饰因子ZNF217存在频繁的体细胞突变。由于ZNF217变异的功能后果尚不清楚，我们全面评估了它们对PMBCL的影响。靶向测序鉴定出影响157例PMBCL患者中33%的ZNF217的遗传损伤。随后的基因表达谱（n=120）揭示了ZNF217异常的PMBCL病例中细胞因子和干扰素信号转导的改变。体外实验发现ZNF217缺失导致染色质可及性的变化，干扰对关键与淋巴瘤相关的转录因子的结合位点的影响。这导致了干扰素响应和炎症相关基因的异常表达，细胞行为的改变和异常分化。质谱分析显示，ZNF217作为包含LSD1、CoREST和HDAC的组蛋白修饰复合物的一部分发挥作用，并干扰H3K4甲基化和H3K27乙酰化。总之，我们的数据表明ZNF217具有非催化活性，可以指导组蛋白修饰复合物的功能，并控制B细胞分化相关的染色质结构模式。© 2023. 作者。

Recent exome-wide studies discovered frequent somatic mutations in the epigenetic modifier ZNF217 in primary mediastinal B cell lymphoma (PMBCL) and related disorders. As functional consequences of ZNF217 alterations remain unknown, we comprehensively evaluated their impact in PMBCL. Targeted sequencing identified genetic lesions affecting ZNF217 in 33% of 157 PMBCL patients. Subsequent gene expression profiling (n = 120) revealed changes in cytokine and interferon signal transduction in ZNF217-aberrant PMBCL cases. In vitro, knockout of ZNF217 led to changes in chromatin accessibility interfering with binding motifs for crucial lymphoma-associated transcription factors. This led to disturbed expression of interferon-responsive and inflammation-associated genes, altered cell behavior, and aberrant differentiation. Mass spectrometry demonstrates that ZNF217 acts within a histone modifier complex containing LSD1, CoREST and HDAC and interferes with H3K4 methylation and H3K27 acetylation. Concluding, our data suggest non-catalytic activity of ZNF217, which directs histone modifier complex function and controls B cell differentiation-associated patterns of chromatin structure.© 2023. The Author(s).