3166 – IRF1 REGULATES SELF-RENEWAL AND STRESS-RESPONSIVENESS TO SUPPORT HEMATOPOIETIC STEM CELL MAINTENANCE

Hematopoietic stem cells (HSCs) reside at the top of the hematopoietic hierarchy and are intricately regulated to support continuous blood cell production whilst maintaining the HSC pool through self-renewal. Inflammatory signaling is key for regulating HSC activity, but the underlying mechanisms and the exact role of various factors during steady-state and stress remain incompletely understood. Interferon (IFN) regulatory factor 1 (IRF1) is a transcription factor at the converge of several inflammatory signaling pathways, including tumor necrosis factor (TNF), RIG-I-like receptor (RLR), Toll-like receptor (TLR), and IFN. It has previously primarily been studied in inflammatory contexts in mature blood cells, where it regulates e.g., immune cell function, pattern recognition receptor (PRR) signaling, NLRP3 and AIM2 inflammasome activation, cell proliferation, apoptosis, and protein degradation. Here, we describe for the first time that IRF1 is a major HSC regulator. We found that IRF1 loss impaired HSC self-renewal, increased stress-induced cell cycle activation, conferred apoptosis resistance, and reduced the expression of MHC class II on the cell surface. Transcriptomic analysis of IRF1-deficient HSCs revealed a complex partially suppressed, partially enhanced inflammatory signature, together with reduced apoptosis and antigen processing and presentation. Prior studies have reported aberrant IRF1 expression in human leukemia. We therefore also explored the potential of IRF1-based acute myeloid leukemia (AML) patient stratification and identified subgroups with distinct cancer-related features. Our findings position IRF1 as a pivotal HSC regulator and paves the way for future investigations into its role in hematologic malignancies. Hematopoietic stem cells (HSCs) reside at the top of the hematopoietic hierarchy and are intricately regulated to support continuous blood cell production whilst maintaining the HSC pool through self-renewal. Inflammatory signaling is key for regulating HSC activity, but the underlying mechanisms and the exact role of various factors during steady-state and stress remain incompletely understood. Interferon (IFN) regulatory factor 1 (IRF1) is a transcription factor at the converge of several inflammatory signaling pathways, including tumor necrosis factor (TNF), RIG-I-like receptor (RLR), Toll-like receptor (TLR), and IFN. It has previously primarily been studied in inflammatory contexts in mature blood cells, where it regulates e.g., immune cell function, pattern recognition receptor (PRR) signaling, NLRP3 and AIM2 inflammasome activation, cell proliferation, apoptosis, and protein degradation. Here, we describe for the first time that IRF1 is a major HSC regulator. We found that IRF1 loss impaired HSC self-renewal, increased stress-induced cell cycle activation, conferred apoptosis resistance, and reduced the expression of MHC class II on the cell surface. Transcriptomic analysis of IRF1-deficient HSCs revealed a complex partially suppressed, partially enhanced inflammatory signature, together with reduced apoptosis and antigen processing and presentation. Prior studies have reported aberrant IRF1 expression in human leukemia. We therefore also explored the potential of IRF1-based acute myeloid leukemia (AML) patient stratification and identified subgroups with distinct cancer-related features. Our findings position IRF1 as a pivotal HSC regulator and paves the way for future investigations into its role in hematologic malignancies.