Tcf1 is essential for initiation of oncogenic Notch1-driven chromatin topology in T-ALL
Antoszewski, Mateusz (Swiss Cancer Center Leman (SCCL) Lausanne, Switzerland)
Fournier, Nadine (Swiss Cancer Center Leman (SCCL) Lausanne, Switzerland)
Ruiz Buendía, Gustavo A. (Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland)
Lourenco, Joao (Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland)
Liu, Yuanlong (Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland)
Sugrue, Tara (University of Basel & ETH Zürich, Basel, Switzerland)
Dubey, Christelle (Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland)
Nkosi, Marianne (Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland)
Pritchard, Colin E.J. (The Netherlands Cancer Institute, Amsterdam, The Netherlands)
Huijbers, Ivo J. (University of Amsterdam, The Netherlands)
Segat, Gabriela C. (Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada)
Alonso-Moreno, Sandra (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Serracanta, Elisabeth (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Belver, Laura (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ferrando, Adolfo A. (Columbia University Medical Center, New York (USA))
Ciriello, Giovanni (Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland)
Weng, Andrew P. (Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada)
Koch, Ute (Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland)
Radtke, Freddy (Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland)

Data:	2022
Resum:	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.
Nota:	Altres ajuts: The Swiss National Science Foundation (SNF 31003A_1467198 and SNF 310030_188505); The Swiss Cancer League; The US National Institutes of Health NIH grants P30 CA013696 and R35 CA210065
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Blood, Vol. 139 Núm. 16 (april 2022) , p. 2483-2498, ISSN 1528-0020

DOI: 10.1182/blood.2021012077
PMID: 35020836

16 p, 6.0 MB

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