Inactivation of Nsd1 impairs terminal erythroid maturation and induces erythroleukemia

S Tauchmann; M Almosailleakh; K Leonards; F Otzen Bagger; S Juge; C Thirant; H Méreau; AHFM Peters; T Mercher; J Schwaller

doi:10.1055/s-0039-1687125

Klinische Pädiatrie, Table of Contents

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

¹University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland

,

M Almosailleakh

¹University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland

,

K Leonards

¹University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland

,

F Otzen Bagger

¹University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland

,

S Juge

¹University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland

,

C Thirant

²INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Paris, France

,

H Méreau

¹University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland

,

AHFM Peters

³Friedrich Miescher Institute for Biomedical Research, Faculty of Sciences, University of Basel, Basel, Switzerland

,

T Mercher

²INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Paris, France

,

J Schwaller

¹University Children's Hospital Basel & Department of Biomedicine, University of Basel, Switzerland

› Author Affiliations

Abstract

Full Text

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.