Klin Padiatr 2019; 231(03): 158
DOI: 10.1055/s-0039-1687125
Abstracts
Georg Thieme Verlag KG Stuttgart · New York

Inactivation of Nsd1 impairs terminal erythroid maturation and induces erythroleukemia

S Tauchmann
1   University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland
,
M Almosailleakh
1   University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland
,
K Leonards
1   University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland
,
F Otzen Bagger
1   University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland
,
S Juge
1   University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland
,
C Thirant
2   INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Paris, France
,
H Méreau
1   University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland
,
AHFM Peters
3   Friedrich Miescher Institute for Biomedical Research, Faculty of Sciences, University of Basel, Basel, Switzerland
,
T Mercher
2   INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Paris, France
,
J Schwaller
1   University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland
› Author Affiliations
Further Information

Publication History

Publication Date:
20 May 2019 (online)

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Nuclear interacting SET domain protein 1 (NSD1) is fused to NUP98 in pediatric AML, however its role in hematopoiesis is unknown. We found that loss of NSD1 altered clonogenic growth of cord blood-derived CD34+ cells leading to accumulation of erythroid progenitors. Ablation of Nsd1 during murine fetal liver hematopoiesis led to a fully penetrant lethal erythroleukemia-like disease. In vitro terminal erythroid maturation of Nsd1-/- erythroblasts was significantly impaired and associated with constitutive expression of the erythroid master regulator GATA1. Retroviral expression of Nsd1, but not a catalytic-inactive mutant rescued the terminal erythroid differentiation of Nsd1-/- erythroblasts associated with upregulation of erythroid regulators on mRNA and protein level. Differentiation of Nsd1-/- erythroblasts was not only associated with increased expression of proposed GATA1 target genes and accompanied by increased GATA1 chromatin binding, but also with reduced interaction to potent transcriptional repressors. Collectively, we identified NSD1 as a regulator of terminal erythroid maturation by controlling the transactivation potential of the erythroid master regulator GATA1.