Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Mus musculus

The transcription factor STAT5 plays a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we demonstrate that STAT5 activation cooperates with defects in the pre-BCR signaling components encoded by Blnk, Btk, Prkcb, Nfkb1, and Ikzf1 to initiate B-ALL. STAT5 antagonizes NF-κB and IKAROS by opposing regulation of shared target genes. STAT5 binding was enriched at super-enhancers, which were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4, and IKAROS. Patients with high ratios of active STAT5 to NF-κB or IKAROS have more aggressive disease. Our studies illustrate that an imbalance of two opposing transcriptional programs drive B-ALL, and suggest that restoring the balance of these pathways may inhibit B-ALL. Overall design: Gene expression profiling was performed on cells isolated from lymph nodes of Stat5b-CA, Stat5b-CA x Blnk+/-, Stat5b-CA x Xid-/-, Stat5b-CA x Pkrcb-/-, Stat5b-CA x Ebf1+/- and Stat5b-CA x Rag2-/- leukemic mice and pre B cells sorted from bone marrow of C57BL/6 wild type mice, Xid Mice, and Stat5b-CA non-leukemic mice. 40 Samples.

转录因子STAT5在B细胞急性淋巴细胞白血病（B-cell acute lymphoblastic leukemia, B-ALL）中发挥关键作用，但其介导该致病效应的具体机制仍未明确。本研究证实，STAT5激活与Blnk、Btk、Prkcb、Nfkb1及Ikzf1编码的前B细胞受体（pre-B cell receptor, pre-BCR）信号组件缺陷协同作用，可启动B-ALL的发生。STAT5通过反向调控共同靶基因，拮抗核因子κB（NF-κB）与IKAROS的功能。STAT5的结合位点在超级增强子（super-enhancer）区域显著富集，这类区域与PAX5、EBF1、PU.1、IRF4及IKAROS等转录因子构成的拮抗调控网络密切相关。活性STAT5与NF-κB或IKAROS的比值较高的患者，其疾病侵袭性更强。本研究表明，两种拮抗转录程序的失衡可驱动B-ALL的发生，并提示恢复这些通路的平衡或可抑制B-ALL。

总体实验设计：对来自Stat5b-CA、Stat5b-CA × Blnk+/-、Stat5b-CA × Xid（X连锁免疫缺陷，X-linked immunodeficiency）-/-、Stat5b-CA × Pkrcb-/-、Stat5b-CA × Ebf1+/-及Stat5b-CA × Rag2-/-白血病模型小鼠淋巴结的细胞进行基因表达谱分析；同时分选C57BL/6野生型小鼠、Xid小鼠及Stat5b-CA非白血病小鼠骨髓中的前B细胞进行分析。本实验共包含40个样本。