Chromatin accessibility profiling of LSK cells with hyperactivated Notch1 and/or Tcf7 knock-out [ATAC-seq_mouse]

NOTCH1 is a well-established lineage specifier for T cells and amongst 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 for aberrant Notch1 signaling to convey its oncogenic function. Although essential, Tcf1 is not sufficient to initiate leukemia. The formation of a leukemia-prone 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 an additional evolutionarily conserved Tcf1-regulated enhancer element, in the distal Myc-enhancer, which is important for the transition of pre-leukemic cells to full-blown disease. ATAC chromatin profile comparisons of sorted LSK derived from C57BL/6J; Sv/129 compound mice with Notch1 induced or Tcf1 knocked-down or NDME…