ETS1 recruits cBAF to hijack the hematopoietic stem cell MYB enhancer in T-cell leukemia [dataset 2]

Notch signaling is the most prevalent oncogenic pathway in T-ALL, but clinical trials showed that pan-Notch inhibitors caused dose-limiting toxicities. Thus, we shifted our focus from Notch to ETS1, which is one of the top transcription factors that most frequently co-bind Notch-occupied regulatory elements in the T-ALL context. A top essential ETS1-dependent element was a Notch-bound enhancer at +140kb from MYB that we named the ETS-MYB enhancer (E-Me). Using genetically engineered mouse models and chromatin profiling, we showed that the E-Me selectively promotes self-renewal of hematopoietic stem cells, becomes inactive in committed T cell progenitors; and is reactivated to promote Notch-induced transformation. ATAC-seq analysis of conventional T-ALL cell lines Cells were treated with DMSO (control) or 500nM dTAGV-1 (treated) for 72 hours prior to submission.

Notch信号通路（Notch signaling）是T细胞急性淋巴细胞白血病（T-ALL）中最常见的致癌通路，但临床试验显示，泛Notch抑制剂会引发剂量限制性毒性。因此，我们将研究重心从Notch转向ETS1——它是在T-ALL背景下，最频繁与结合了Notch的调控元件发生共结合的顶级转录因子之一。我们鉴定出一个关键的、依赖ETS1的核心调控元件：位于MYB基因+140kb位点处的结合了Notch的增强子，我们将其命名为ETS-MYB增强子（E-Me）。借助基因工程小鼠模型与染色质谱分析技术，我们证实E-Me可选择性促进造血干细胞的自我更新，在定型T细胞祖细胞中处于失活状态，且可被重新激活以介导Notch诱导的致癌转化。针对常规T-ALL细胞系的ATAC-seq分析显示：在样本提交检测前，细胞已用二甲基亚砜（DMSO，对照组）或500nM dTAGV-1（处理组）处理72小时。