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

Katharina Leonards, Marwa Almosailleakh, Samantha Tauchmann, Frederik Otzen Bagger, Cécile Thirant, Sabine Juge, Thomas Bock, Hélène Méreau, Matheus F. Bezerra, Alexandar Tzankov, Robert Ivanek, Régine Losson, Antoine H. F. M. Peters, Thomas Mercher and Juerg Schwaller ()
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Katharina Leonards: University Children’s Hospital Basel
Marwa Almosailleakh: University Children’s Hospital Basel
Samantha Tauchmann: University Children’s Hospital Basel
Frederik Otzen Bagger: University Children’s Hospital Basel
Cécile Thirant: Université Paris-Sud
Sabine Juge: University Children’s Hospital Basel
Thomas Bock: Biozentrum University of Basel
Hélène Méreau: University of Basel
Matheus F. Bezerra: University Children’s Hospital Basel
Alexandar Tzankov: University Hospital Basel
Robert Ivanek: University of Basel
Régine Losson: CNRS/INSERM Université de Strasbourg
Antoine H. F. M. Peters: Friedrich Miescher Institute for Biomedical Research
Thomas Mercher: Université Paris-Sud
Juerg Schwaller: University Children’s Hospital Basel

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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 NSD1N1918Q SET-domain mutant induces terminal maturation of Nsd1−/− erythroblasts. Despite similar GATA1 protein levels, exogenous NSD1 but not NSDN1918Q 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.

Date: 2020
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DOI: 10.1038/s41467-020-16179-8

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