The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of . We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin co-accessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling and negative control of proliferation by T-bet. In line, we showed that T-bet represses cell cycling and is associated with longer overall survival of patients with CLL. Our study uncovered a novel tumor suppressive role of T-bet in malignant B cells via its regulation of inflammatory processes and cell cycling, which has implications for the stratification and therapy of patients with CLL. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in the inflammatory signaling pathways in CLL.

中文翻译：

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T-bet 抑制慢性淋巴细胞白血病中恶性 B 细胞的增殖

T-box 转录因子 T-bet 被认为是 T 细胞反应的主要调节因子，但其在恶性 B 细胞中的作用尚未得到充分探索。在这里，我们对慢性淋巴细胞白血病 (CLL) 患者的恶性 B 细胞进行了单细胞解析多组学分析，并研究了 基因敲除的 CLL 小鼠模型。我们发现 T-bet 通过降低恶性 B 细胞的增殖率来充当肿瘤抑制剂。由微环境提供的炎症信号诱导的 NF-κB 活性触发 T-bet 表达，影响启动子近端和远端染色质的共可达性，并主要通过抑制转录来控制特定的基因特征。基因集富集分析确定了 T-bet 对干扰素信号传导的正向调节和对增殖的负向控制。与此一致，我们发现 T-bet 可以抑制细胞周期，并且与 CLL 患者更长的总生存期相关。我们的研究揭示了 T-bet 通过调节炎症过程和细胞周期在恶性 B 细胞中发挥的新型肿瘤抑制作用，这对 CLL 患者的分层和治疗具有重要意义。将 T-bet 活动与炎症联系起来解释了 CLL 炎症信号通路中基因改变的良好预后作用。