PU.1 as a Master Regulator of Immune Cell Development and Function: Structural Basis, Gene Regulatory Networks, Disease Roles, and Therapeutic Targeting.

PU.1 is a hematopoietic ETS-family transcription factor that serves as a master regulator of immune cell development, lineage commitment, chromatin organization, and innate immune function. PU.1 is essential for the generation and maintenance of monocytes, macrophages, dendritic cells, granulocytes, and B lymphocytes, while its repression is required for T-cell lineage commitment. As a lineage-determining transcription factor, PU.1 establishes cell identity by binding enhancer elements, recruiting chromatin remodelers, and cooperating with partner factors such as C/EBPα, RUNX1, IRF8, and GATA factors. Tight quantitative control of PU.1 is critical, as both reduced and excessive activity can disrupt hematopoiesis and immunity. Dysregulation of PU.1 has been implicated in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), lymphoid malignancies, chronic inflammatory disorders, fibrosis, and neurodegenerative disease. Recent structural and mechanistic advances have provided insights into the structure of PU.1, DNA recognition specificity, post-transcriptional regulation, and therapeutic vulnerabilities. In this review, we summarize current knowledge of PU.1 protein structure, regulatory mechanisms, binding partners, roles in disease, and emerging strategies to therapeutically target PU.1-centered networks.