文章：

B细胞受体信号通过直接增强子调控驱动慢性淋巴细胞白血病B细胞中APOBEC3的表达

B cell receptor signaling drives APOBEC3 expression via direct enhancer regulation in chronic lymphocytic leukemia B cells

原文发布日期：2022-07-01

DOI: 10.1038/s41408-022-00690-w

类型: Article

开放获取: 是

英文摘要：

Constitutively activated B cell receptor (BCR) signaling is a primary biological feature of chronic lymphocytic leukemia (CLL). The biological events controlled by BCR signaling in CLL are not fully understood and need investigation. Here, by analysis of the chromatin states and gene expression profiles of CLL B cells from patients before and after Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib treatment, we show that BTKi treatment leads to a decreased expression of APOBEC3 family genes by regulating the activity of their enhancers. BTKi treatment reduces enrichment of enhancer marks (H3K4me1 and H3K27ac) and chromatin accessibility at putative APOBEC3 enhancers. CRISPR-Cas9 directed deletion or inhibition of the putative APOBEC3 enhancers leads to reduced APOBEC3 expression. We further find that transcription factor NFATc1 couples BCR signaling with the APOBEC3 enhancer activity to control APOBEC3 expression. We also find that enhancer-regulated APOBEC3 expression contributes to replication stress in malignant B cells. In total we demonstrate a novel mechanism for BTKi suppression of APOBEC3 expression via direct enhancer regulation in an NFATc1-dependent manner, implicating BCR signaling as a potential regulator of leukemic genomic instability.
 

摘要翻译： 

持续活化的B细胞受体（BCR）信号通路是慢性淋巴细胞白血病（CLL）的主要生物学特征。目前对于BCR信号在CLL中所调控的生物学事件尚未完全明确，有待进一步研究。本研究通过分析患者在接受布鲁顿酪氨酸激酶抑制剂（BTKi）伊布替尼治疗前后的CLL B细胞染色质状态及基因表达谱，发现BTKi治疗通过调控增强子活性降低了APOBEC3家族基因的表达。BTKi处理减少了推定的APOBEC3增强子区域上增强子标记（H3K4me1和H3K27ac）的富集程度及染色质可及性。通过CRISPR-Cas9定向敲除或抑制这些推定的APOBEC3增强子会导致APOBEC3表达下降。我们进一步发现转录因子NFATc1将BCR信号通路与APOBEC3增强子活性相耦合，从而调控APOBEC3表达。研究还表明，增强子调控的APOBEC3表达促进了恶性B细胞的复制应激。总体而言，我们揭示了BTKi通过以NFATc1依赖的方式直接调控增强子来抑制APOBEC3表达的新机制，这提示BCR信号通路可能是白血病基因组不稳定的潜在调节因子。

原文链接：

B cell receptor signaling drives APOBEC3 expression via direct enhancer regulation in chronic lymphocytic leukemia B cells