Tcf1 is essential for initiation of oncogenic Notch1-driven chromatin topology in T-ALL

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 de...

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Published in:Blood 2022-04, Vol.139 (16), p.2483-2498
Main Authors: Antoszewski, Mateusz, Fournier, Nadine, Ruiz Buendía, Gustavo A., Lourenco, Joao, Liu, Yuanlong, Sugrue, Tara, Dubey, Christelle, Nkosi, Marianne, Pritchard, Colin E.J., Huijbers, Ivo J., Segat, Gabriela C., Alonso-Moreno, Sandra, Serracanta, Elisabeth, Belver, Laura, Ferrando, Adolfo A., Ciriello, Giovanni, Weng, Andrew P., Koch, Ute, Radtke, Freddy
Format: Article
Language:English
Subjects:
Carcinogenesis - genetics
Cell Line, Tumor
Chromatin - genetics
Humans
Lymphoid Neoplasia
Oncogenes
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Receptor, Notch1 - genetics
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Summary: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. •Tcf1 shapes a Notch1-induced T-ALL-prone chromatin landscape in early hematopoietic progenitors.•Tcf1 orchestrates chromatin accessibility within the Notch1-regulated Myc super-enhancer. [Display omitted]
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2021012077