Journal Article

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

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

2020

Overview

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. Loss of function mutations of NSD1 occur in blood cancers. Here, the authors report that NSD1 loss blocks erythroid differentiation which leads to an erythroleukemia-like disease in mice by impairing GATA1-induced target gene activation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/15 / 38/77 / 38/88 / 38/89 / 38/91 / 45 / 45/15 / 631/67/1990/283/1897 / 64 / 64/60 / 692/4017 / 82/58 / 82/80 / 96 / 96/106 / 96/21 / 96/31 / Ablation / Activation / Adult / Animals / Antigens, CD - metabolism / Antigens, CD34 - metabolism / Biochemistry, Molecular Biology / Blood cancer / Cancer / CD34 antigen / Cell Differentiation / Cell Line, Tumor / Cell Lineage / Chromatin - metabolism / Deactivation / Differentiation / DNA-Binding Proteins - metabolism / Erythroblasts / Erythroblasts - metabolism / Erythroid Cells - metabolism / Erythroid Cells - pathology / Erythroleukemia / Erythropoiesis / GATA-1 protein / GATA1 Transcription Factor - genetics / GATA1 Transcription Factor - metabolism / Gene expression / Gene Expression Regulation, Leukemic / Gene Knockdown Techniques / Hematological diseases / Hematology / Hematopoiesis / Hematopoietic system / Histone-Lysine N-Methyltransferase - genetics / Histone-Lysine N-Methyltransferase - metabolism / Human health and pathology / Humanities and Social Sciences / Humans / Inactivation / Kaplan-Meier Estimate / Kinases / Leukemia / Leukemia, Erythroblastic, Acute - genetics / Leukemia, Erythroblastic, Acute - metabolism / Leukemia, Erythroblastic, Acute - pathology / Leukemogenesis / Life Sciences / Male / Methyltransferase / Mice / Molecular biology / multidisciplinary / Mutation / Occupancy / Protein Binding / Proteins / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins c-kit - metabolism / Receptors, Transferrin - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Ski protein / Transcription