Distal enhancers play critical roles in sustaining oncogenic gene expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+ B-ALL "signature" genes, including likely oncogenic drivers. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of many repeat enhancer-activated genes. Together, our findings reveal a novel epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene expression program of ETV6-RUNX1+ B-ALL.

中文翻译：

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ETV6缺乏和微卫星增强剂驱动B淋巴细胞白血病的转录失调

远端增强剂在维持致癌基因表达程序中起关键作用。我们将 GGAA 串联重复序列的异常增强子样激活确定为 B 细胞急性淋巴细胞白血病 (B-ALL) 的特征性特征，其具有 ETV6 转录抑制因子的遗传缺陷，包括 ETV6-RUNX1+ 和 ETV6-null B-ALL。我们表明，GGAA 重复增强子是先前确定的 ETV6-RUNX1+ B-ALL“签名”基因的直接激活剂，包括可能的致癌驱动因素。当恢复到 ETV6 缺陷型 B-ALL 细胞时，ETV6 直接与 GGAA 重复增强子结合，抑制其乙酰化，下调相邻基因，并抑制 B-ALL 生长。在 ETV6 缺陷型 B-ALL 细胞中，我们发现 ETS 转录因子 ERG 直接与 GGAA 微卫星增强子结合，是许多重复增强子激活基因持续激活所必需的。总之，我们的研究结果揭示了 ETV6 肿瘤抑制基因的一种新的表观遗传看门人功能，并将微卫星增强子确立为 ETV6-RUNX1+ B-ALL 独特基因表达程序的关键机制。