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

Katharina Leonards,Sabine Juge,Thomas Bock,Frederik Otzen Bagger,Antoine H F M Peters,Marwa Almosailleakh,Juerg Schwaller,Hélène Méreau,Robert Ivanek,Régine Losson,Alexandar Tzankov,Matheus F Bezerra,Cécile Thirant,Thomas Mercher,Samantha Tauchmann

doi:10.1038/s41467-020-16179-8

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.

Highlights

The nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia
Inactivation studies in mice revealed that GATA1 is an essential master regulator of erythropoiesis as Gata1-null embryos died in utero from anemia[4]
We identified three NSD1 shRNA that reduced the numbers of colonies grown in methylcellulose (MC) containing growth factors including EPO (Fig. 1a, b, Supplementary Fig. 1a, b)

Summary

Introduction

The nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. Erythroid differentiation is mainly regulated by a relatively small number of transcriptional regulators, including GATA-1, SCL/TAL1, LMO2, LDB1, KLF1, and GFI1b, that dynamically form multiprotein complexes It remains poorly understood how distinct complexes interact and activate or repress specific gene expression programs[2]. Some adult female mice that are heterozygous for the targeted disruption of the X chromosome-linked Gata[1] promoter region displayed reduced Gata[1] gene expression (Gata11.05/X allele) and developed an early onset erythroleukemia-like disease[5] This mouse model suggested that reduced Gata[1] activity contributes to leukemogenesis by preventing proper erythroid differentiation. Our work suggests that NSD1 controls target gene activation by the erythroid master regulator GATA1, most likely through regulated association with the transcriptional co-repressor SKI. We identify NSD1 as a co-regulator of GATA1-controlled terminal erythroid maturation and leukemogenesis

Methods

Results

Conclusion