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IRF1 regulates self-renewal and stress responsiveness to support hematopoietic stem cell maintenance

Rundberg Nilsson, Alexandra J.S. LU ; Xian, Hongxu ; Shalapour, Shabnam ; Cammenga, Jörg LU and Karin, Michael (2023) In Science Advances 9(43).
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... (More)

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.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
9
issue
43
article number
eadg5391
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:37889967
  • scopus:85175279379
ISSN
2375-2548
DOI
10.1126/sciadv.adg5391
language
English
LU publication?
yes
id
892b48b6-8712-4c20-9372-2a671a18b5a1
date added to LUP
2023-12-11 14:41:25
date last changed
2024-04-24 08:08:47
@article{892b48b6-8712-4c20-9372-2a671a18b5a1,
  abstract     = {{<p>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.</p>}},
  author       = {{Rundberg Nilsson, Alexandra J.S. and Xian, Hongxu and Shalapour, Shabnam and Cammenga, Jörg and Karin, Michael}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  number       = {{43}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{IRF1 regulates self-renewal and stress responsiveness to support hematopoietic stem cell maintenance}},
  url          = {{http://dx.doi.org/10.1126/sciadv.adg5391}},
  doi          = {{10.1126/sciadv.adg5391}},
  volume       = {{9}},
  year         = {{2023}},
}