IRF1 Regulates Self-Renewal and Stress Responsiveness to Support Hematopoietic Stem Cell Maintenance

Authors

Alexandra J S Rundberg Nilsson
Hongxu Xian
Shabnam Shalapour
Jörg Cammenga
Michael Karin

Publication Date

10-27-2023

Journal

Science Advances

Abstract

Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions of specific factors under steady-state and stress conditions remain incompletely understood. We investigated the role of interferon regulatory factor 1 (IRF1), a transcription factor that is affected by multiple inflammatory stimuli, in HSC regulation. Our findings demonstrate that the loss of IRF1 from mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis. In addition, given the frequent abnormal expression of IRF1 in leukemia, we explored the potential of IRF1 expression level as a stratification marker for human acute myeloid leukemia. We show that IRF1-based stratification identifies distinct cancer-related signatures in patient subgroups. These findings establish IRF1 as a pivotal HSC controller and provide previously unknown insights into HSC regulation, with potential implications to IRF1 functions in the context of leukemia.

Keywords

Mice, Humans, Animals, Interferon Regulatory Factor-1, Gene Expression Regulation, Signal Transduction, Leukemia, Myeloid, Acute, Hematopoietic Stem Cells, Cell Differentiation, Cell Proliferation

DOI

10.1126/sciadv.adg5391

PMID

37889967

PMCID

PMC10610924

PubMedCentral® Posted Date

10-27-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes