PRDM15 regulates differentiation and proliferation of hematopoietic stem cells.

Hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis through a tightly regulated balance of self-renewal, proliferation and differentiation, particularly under stress conditions. Here, we identify PRDM15, a transcription factor with well described roles in early embryonic development, as a crucial regulator of hematopoiesis during stress responses. While PRDM15 deletion is tolerated at steady state in adult hematopoiesis, its absence severely impairs bone marrow reconstitution following transplantation, causing sustained reduction in bone marrow cellularity and differentiation blocks. Notably, PRDM15-deleted bone marrow exhibited an accumulation of stem and progenitor cells, indicating a block in lineage differentiation. Furthermore, in competitive transplantation assays, PRDM15-deficient cells were unable to compete with wild-type counterparts, demonstrating a profound loss of fitness. Transcriptomic and epigenomic analyses reveal PRDM15 as a critical regulator of differentiation and proliferation of HSCs. Mechanistically, PRDM15 directly regulates the expression of several key genes involved in proliferation and differentiation pathways, including the transcription factor Cux1. Cux1 overexpression partially rescues colony-forming ability of PRDM15-deficient HSCs. These findings establish PRDM15 as a pivotal stress-responsive regulator of HSC differentiation and survival, with implications for therapeutic modulation of hematopoiesis.