NOTCH1 is a well-established lineage specifier for T cells and among the most frequently mutated genes throughout all subclasses of T cell acute lymphoblastic leukemia (T-ALL). How oncogenic NOTCH1 signaling launches a leukemia-prone chromatin landscape during T-ALL initiation is unknown. Here we demonstrate an essential role for the high-mobility-group transcription factor Tcf1 in orchestrating chromatin accessibility and topology, allowing aberrant Notch1 signaling to convey its oncogenic function. Although essential, Tcf1 is not sufficient to initiate leukemia. The formation of a leukemia-prone epigenetic landscape at the distal Notch1-regulated Myc enhancer, which is fundamental to this disease, is Tcf1-dependent and occurs within the earliest progenitor stage even before cells adopt a T lymphocyte or leukemic fate. Moreover, we discovered a unique evolutionarily conserved Tcf1-regulated enhancer element in the distal Myc-enhancer, which is important for the transition of preleukemic cells to full-blown disease.

中文翻译：

---

Tcf1 对于 T-ALL 中 Notch1 驱动的致癌染色质拓扑的启动至关重要。


NOTCH1 是 T 细胞的成熟谱系标记，也是 T 细胞急性淋巴细胞白血病 (T-ALL) 所有亚类中最常见的突变基因之一。在 T-ALL 启动过程中，致癌性 NOTCH1 信号如何启动易患白血病的染色质景观尚不清楚。在这里，我们证明了高迁移率组转录因子 Tcf1 在协调染色质可及性和拓扑结构方面的重要作用，允许异常的 Notch1 信号传递其致癌功能。尽管 Tcf1 很重要，但它不足以引发白血病。在远端 Notch1 调节的 Myc 增强子上形成易患白血病的表观遗传景观是这种疾病的基础，它依赖于 Tcf1，并且发生在最早的祖细胞阶段，甚至在细胞采取 T 淋巴细胞或白血病命运之前。此外，我们在远端Myc增强子中发现了一个独特的进化保守的Tcf1调节增强子元件，这对于白血病前期细胞向成熟疾病的转变非常重要。