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; Juerg Schwaller

doi:10.1038/s41467-020-16179-8

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

Nat Commun. 2020 Jun 12;11(1):2807. doi: 10.1038/s41467-020-16179-8.

Authors

Katharina Leonards^#^{1

2}, Marwa Almosailleakh^#^{1

2}, Samantha Tauchmann^#^{1

2}, Frederik Otzen Bagger^#^{1

2

3

4}, Cécile Thirant⁵, Sabine Juge^{1

2}, Thomas Bock⁶, Hélène Méreau², Matheus F Bezerra^{1

2

7}, Alexandar Tzankov⁸, Robert Ivanek^{2

3}, Régine Losson⁹, Antoine H F M Peters^{10

11}, Thomas Mercher⁵, Juerg Schwaller^{12

13}

Affiliations

¹ University Children's Hospital Basel, Basel, Switzerland.
² Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.
³ Swiss Institute of Bioinfomatics, 4031, Basel, Switzerland.
⁴ Genomic Medicine, Righospitalet, University of Copenhagen, 2100, Copenhagen, Denmark.
⁵ INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Université Paris-Sud, Villejuif, 94800, France.
⁶ Proteomics Core Facility, Biozentrum University of Basel, Basel, Switzerland.
⁷ Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil.
⁸ Institute for Pathology, University Hospital Basel, 4031, Basel, Switzerland.
⁹ Institute de Génétique et de Biologie Moléculaire et Cellulaire (I.G.B.M.C.), CNRS/INSERM Université de Strasbourg, BP10142, 67404, Illkirch Cedex, France.
¹⁰ Friedrich Miescher Institute for Biomedical Research, 4058, Basel, Switzerland.
¹¹ Faculty of Sciences, University of Basel, 4056, Basel, Switzerland.
¹² University Children's Hospital Basel, Basel, Switzerland. J.Schwaller@unibas.ch.
¹³ Department of Biomedicine, University of Basel, 4031, Basel, Switzerland. J.Schwaller@unibas.ch.

^# Contributed equally.

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Antigens, CD / metabolism
Antigens, CD34 / metabolism
Cell Differentiation*
Cell Line, Tumor
Cell Lineage
Chromatin / metabolism
DNA-Binding Proteins / metabolism
Erythroblasts / metabolism
Erythroid Cells / metabolism*
Erythroid Cells / pathology*
GATA1 Transcription Factor / genetics
GATA1 Transcription Factor / metabolism*
Gene Expression Regulation, Leukemic
Gene Knockdown Techniques
Hematopoiesis
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Humans
Kaplan-Meier Estimate
Leukemia, Erythroblastic, Acute / genetics
Leukemia, Erythroblastic, Acute / metabolism*
Leukemia, Erythroblastic, Acute / pathology*
Male
Mice
Protein Binding
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-kit / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Transferrin / metabolism

Substances

Antigens, CD
Antigens, CD34
CD71 antigen
Chromatin
DNA-Binding Proteins
GATA1 Transcription Factor
Proto-Oncogene Proteins
RNA, Messenger
Receptors, Transferrin
SKI protein, human
Histone-Lysine N-Methyltransferase
NSD1 protein, human
Nsd1 protein, mouse
Proto-Oncogene Proteins c-kit