Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia.

Autor: Leonards K; University Children's Hospital Basel, Basel, Switzerland.; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland., Almosailleakh M; University Children's Hospital Basel, Basel, Switzerland.; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland., Tauchmann S; University Children's Hospital Basel, Basel, Switzerland.; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland., Bagger FO; University Children's Hospital Basel, Basel, Switzerland.; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.; Swiss Institute of Bioinfomatics, 4031, Basel, Switzerland.; Genomic Medicine, Righospitalet, University of Copenhagen, 2100, Copenhagen, Denmark., Thirant C; INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Université Paris-Sud, Villejuif, 94800, France., Juge S; University Children's Hospital Basel, Basel, Switzerland.; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland., Bock T; Proteomics Core Facility, Biozentrum University of Basel, Basel, Switzerland., Méreau H; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland., Bezerra MF; University Children's Hospital Basel, Basel, Switzerland.; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.; Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil., Tzankov A; Institute for Pathology, University Hospital Basel, 4031, Basel, Switzerland., Ivanek R; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.; Swiss Institute of Bioinfomatics, 4031, Basel, Switzerland., Losson R; Institute de Génétique et de Biologie Moléculaire et Cellulaire (I.G.B.M.C.), CNRS/INSERM Université de Strasbourg, BP10142, 67404, Illkirch Cedex, France., Peters AHFM; Friedrich Miescher Institute for Biomedical Research, 4058, Basel, Switzerland.; Faculty of Sciences, University of Basel, 4056, Basel, Switzerland., Mercher T; INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Université Paris-Sud, Villejuif, 94800, France., Schwaller J; University Children's Hospital Basel, Basel, Switzerland. J.Schwaller@unibas.ch.; Department of Biomedicine, University of Basel, 4031, Basel, Switzerland. J.Schwaller@unibas.ch.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Jun 12; Vol. 11 (1), pp. 2807. Date of Electronic Publication: 2020 Jun 12.
DOI: 10.1038/s41467-020-16179-8
Abstrakt: The nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We show that NSD1 knockdown alters erythroid clonogenic growth of human CD34 + hematopoietic cells. Ablation of Nsd1 in the hematopoietic system of mice induces a transplantable erythroleukemia. In vitro differentiation of Nsd1 -/- erythroblasts is majorly impaired despite abundant expression of GATA1, the transcriptional master regulator of erythropoiesis, and associated with an impaired activation of GATA1-induced targets. Retroviral expression of wildtype NSD1, but not a catalytically-inactive NSD1 N1918Q SET-domain mutant induces terminal maturation of Nsd1 -/- erythroblasts. Despite similar GATA1 protein levels, exogenous NSD1 but not NSD N1918Q significantly increases the occupancy of GATA1 at target genes and their expression. Notably, exogenous NSD1 reduces the association of GATA1 with the co-repressor SKI, and knockdown of SKI induces differentiation of Nsd1 -/- erythroblasts. Collectively, we identify the NSD1 methyltransferase as a regulator of GATA1-controlled erythroid differentiation and leukemogenesis.
Databáze: MEDLINE
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