A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage
Open accessAbstract
Checkpoints that limit stem cell self-renewal in response to DNA damage can contribute to cancer protection but may also promote tissue aging. Molecular components that control stem cell responses to DNA damage remain to be delineated. Using in vivo RNAi screens, we identified basic leucine zipper transcription factor, ATF-like (BATF) as a major component limiting self-renewal of hematopoietic stem cells (HSCs) in response to telomere dysfunction and γ-irradiation. DNA damage induces BATF in a G-CSF/STAT3-dependent manner resulting in lymphoid differentiation of HSCs. BATF deletion improves HSC self-renewal and function in response to γ-irradiation or telomere shortening but results in accumulation of DNA damage in HSCs. Analysis of bone marrow from patients with myelodysplastic syndrome supports the conclusion that DNA damage-dependent induction of BATF is conserved in human HSCs. Together, these results provide experimental evidence that a BATF-dependent differentiation checkpoint limits self-renewal of HSCs in response to DNA damage.
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Lymphoid-biased hematopoietic stem cells in old mice accumulate defects that may impair self-renewal and contribute to their decline.
“Lymphoid-biased HSCs in old mice also appear to accumulate deficiencies that, as discussed below, may compromise their selfrenewal potential and contribute to the decline of this population (27).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [27]
This provides a molecular mechanism for the age-related decline in lymphoid-biased hematopoietic stem cell number.
“This is a particularly interesting finding, because it provides a molecular mechanism for the age-related decline in the number of lymphoid-biased HSCs discussed above.”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [27]
BATF levels increase in hematopoietic stem cells in response to DNA damage, causing lymphoid-biased stem cells to differentiate at the expense of self-renewal.
“Wang and colleagues demonstrated that BATF levels increased in HSCs in response to DNA damage and that this resulted in the differentiation of lymphoid-biased HSCs at the expense of their self-renewal (27).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [27]
Induction of HSC differentiation in response to IR-induced DNA damage via activation of the G-CSF/Stat3/BATF-dependent differentiation checkpoint contributes to IR-induced myeloid-skewed HSCs by selectively depleting lymphoid-biased HSCs.
“induction of HSC differentiation in response to IR-induced DNA damage via activation of the granulocyte colony-stimulating factor/Stat3/BATF–dependent differentiation checkpoint also contribute to IR-induced myeloid-skewed HSCs by selectively depleting lymphoid-biased HSCs, as was recently reported.31”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [31]
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- Authors
- Wang, J., Sun, Q., Morita, Y., Jiang, H., Groß, A., Lechel, A., Hildner, K., Guachalla, L. M., Gompf, A., Hartmann, D., Schambach, A., Wuestefeld, T., Dauch, D., Schrezenmeier, H., Hofmann, W.-K., Nakauchi, H., Ju, Z., Kestler, H. A., Zender, L., & Rudolph, K. L.
- Affiliations
- Universität Ulm (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Medizinische Hochschule Hannover (DE)
- University of Mannheim (DE)
- Japan Science and Technology Agency (JP)
- Hangzhou Normal University (CN)
- Corresponding author
- Rudolph, K. Lenhard
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 148
- Issue
- 5
- Pages
- 1001-1014
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2167167418
- Semantic Scholar
- 8f93eb799dfb8f593e0e7153ef0c94a3a0545134
- Cited by
- 343
- References
- 60
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 20 · 2023: 10 · 2022: 11 · 2021: 13 · 2020: 27 · 2019: 20 · 2018: 26 · 2017: 26 · 2016: 34 · 2015: 38 · 2014: 42 · 2013: 31 · 2012: 21
- FWCI
- 27.90
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-09-11)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (22659058)
- International Graduate School in Molecular Medicine Ulm
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- hematopoietic stem cells, stem cell self-renewal, DNA damage response, BATF, lymphoid differentiation, telomere dysfunction, gamma irradiation, myelodysplastic syndrome, bone marrow, tissue aging
- MeSH terms
- Animals, Cell Differentiation, DNA Damage, Hematopoietic Stem Cells, Humans, Mice, Inbred C57BL, Specific Pathogen-Free Organisms, Cellular Senescence, Mice, Cell Cycle Checkpoints, Telomere Shortening
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