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.

组成型激活的 B 细胞受体 (BCR) 信号传导是慢性淋巴细胞白血病 (CLL) 的主要生物学特征。 CLL 中 BCR 信号传导控制的生物学事件尚未完全了解，需要研究。在这里，通过分析 Bruton 酪氨酸激酶抑制剂 (BTKi) 依鲁替尼治疗前后患者 CLL B 细胞的染色质状态和基因表达谱，我们发现 BTKi 治疗通过调节 APOBEC3 家族基因的活性，导致 APOBEC3 家族基因的表达降低。他们的增强剂。 BTKi 处理会降低增强子标记（H3K4me1 和 H3K27ac）的富集以及假定的 APOBEC3 增强子的染色质可及性。 CRISPR-Cas9 定向删除或抑制假定的 APOBEC3 增强子会导致 APOBEC3 表达减少。我们进一步发现转录因子 NFATc1 将 BCR 信号传导与 APOBEC3 增强子活性结合以控制 APOBEC3 表达。我们还发现增强子调节的 APOBEC3 表达有助于恶性 B 细胞的复制应激。总的来说，我们证明了 BTKi 通过以 NFATc1 依赖性方式直接增强子调节来抑制 APOBEC3 表达的新机制，这表明 BCR 信号传导是白血病基因组不稳定性的潜在调节因子。