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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.

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