The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Abstract
The 'ataxia telangiectasia mutated' (Atm) gene maintains genomic stability by activating a key cell-cycle checkpoint in response to DNA damage, telomeric instability or oxidative stress. Mutational inactivation of the gene causes an autosomal recessive disorder, ataxia-telangiectasia, characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature ageing and a high incidence of lymphoma. Here we show that ATM has an essential function in the reconstitutive capacity of haematopoietic stem cells (HSCs) but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm-/- mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in HSC function that was associated with elevated reactive oxygen species. Treatment with anti-oxidative agents restored the reconstitutive capacity of Atm-/- HSCs, resulting in the prevention of bone marrow failure. Activation of the p16(INK4a)-retinoblastoma (Rb) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm-/- HSCs. These results show that the self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress.
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In the citing paper
“other studies have shown the potential of antioxidants to improve the function of old HSCs (76,96).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [96]
In the citing paper
“in HSCs and neural stem cells (NSCs) of mice, excessive cellular ROS concentrations lead to abnormal proliferation, malignancy and compromised stem cell self-renewal11–14”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“experimentally induced genetic disruption of DDR pathways in mice also produces cell-autonomous defects in HSC function, as assayed by in vivo hematopoietic reconstitution and in vitro colony forming assays11,36,52,53.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“age-dependent alterations in regulation of SOD2 by FoxO3 and the DNA damage sensing serine/threonine protein kinase ATM (ataxia-telangiectasia mutated) have been shown to contribute to loss of HSC function with aging11,16, 24.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“Another potential function for ATM in suppressing progeroid phenotypes may be related to reported ATM functions in regulating intracellular ROS levels and sensitivity to these molecules (Barzilai et al., 2002; Ito et al., 2004”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Ito et al., 2004
In the citing paper
“Inactivation of the p16-Rb pathway restores the reproductive function of ATM−/− HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.20,21”
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 [20]
In the citing paper
“Furthermore, mutation of the ataxia telangiectasia mutated (ATM) gene also results in upregulation of p16 and Arf in HSCs.”
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 [20]
In the citing paper
“ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.15,19,20,35-38”
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 [20]
In the citing paper
“mice lacking Atm show rapid ageing and depletion of their haematopoietic stem cell compartment 34”
From The common biology of cancer and ageing (2007) · cites this paper as [34]
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BackgroundRegulation of Reactive Oxygen Species and Genomic Stability in Hematopoietic Stem Cells
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BackgroundAn MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate
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“ATM might prevent cumulative DNA lesions by quenching reactive oxygen species”
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“Similarly, it has been reported recently that ATM-/- mice have a defect in HSC self-renewal and exhibit a progressive decline in HSCs with age [69].”
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“Several recent studies also showed that induction of oxidative stress was primarily responsible for the loss of HSC self-renewal and premature exhaustion of HSCs in mice with mutations in the ATM [6] and deletion of Forkhead box O3 (FoxO3) [7].”
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“ROS levels are also thought to be regulated by ATM, and indeed, loss of Atm leads to diminished HSC function resulting from ROS-mediated activation of mitogen-activated protein kinase p38 and cyclin-dependent kinase inhibitor 2A (CDKN2A; also known as p16INK4a), leading to cell cycle arres”
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BackgroundEtoposide Induces ATM-Dependent Mitochondrial Biogenesis through AMPK Activation
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“We were unable to detect FoxO3a inactivation or a significant increase in ROS levels in HSCs after Pten deletion.”
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BackgroundSelf-citationA ROS rheostat for cell fate regulation
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“Stem cell self-renewal is sensitive to oxidative stress (Ito et al., 2004) and FOXOs help maintain stem cells by preventing the accumulation of ROS, which can disrupt genomic and protein integrity.”
BackgroundATM activation in the presence of oxidative stress
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“Recent findings in Bmi-1–, ATM-, and JunB-deficient mice underscore the impact of G1-S regulation by p16INK4a and p19ARF in HSC self-renewal (4, 13, 35).”
BackgroundReactive Oxygen Species and Mitochondrial Homeostasis as Regulators of Stem Cell Fate and Function
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“Notably, ROS-induced activation of p38-MAPK in HSPCs was dependent on ASK1 (53).”
InfluentialSelf-citationOxidative Stress Regulation of Stem and Progenitor Cells
Pervaiz, S., Taneja, R., & Ghaffari, S. (2009) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2804 · Cited by 176
“Loss of ATM also results in ROS-mediated depletion of hematopoietic stem cell pool, leading to bone marrow failure in old mice (48).”
The ATM signaling network in development and disease
Stracker, T. H., Roig, I., Knobel, P. A., & Marjanović, M. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00037 · Cited by 192
“ATM-deficient mice that escape lymphoma development exhibited progressive bone marrow failure that was rescued by treatment with antioxidants or the inhibition of p38 mitogen-activated protein kinase (p38MAPKs; Ito et al., 2004, 2006).”
BackgroundInfluentialUnwin, R. D., Smith, D. L., Blinco, D., Wilson, C., Miller, C. J., Evans, C. A., Jaworska, E., Baldwin, S. A., Barnes, K., Pierce, A., et al. (2006) · Blood · doi:10.1182/blood-2005-12-4995 · Cited by 178
Regulation of Hematopoiesis and Osteogenesis by Blood Vessel–Derived Signals
Ramasamy, S. K., Kusumbe, A. P., Itkin, T., Gur‐Cohen, S., Lapidot, T., & Adams, R. H. (2016) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-111315-124936 · Cited by 176
“ROS are pivotal HSC regulators serving as a metabolic feedback loop to control HSC repopulation potential, quiescence, self-renewal, proliferation, maintenance, and life span (Itkin et al. 2012, 2013; Ito et al. 2004, 2006; Ludin et al. 2012; Miyamoto et al. 2007; Takubo et al. 2013).”
BackgroundEffect of atmospheric gas plasmas on cancer cell signaling
Ishaq, M., Evans, M. D. M., & Ostrikov, K. (2013) · International Journal of Cancer · doi:10.1002/ijc.28323 · Cited by 169
Redox regulation of stem/progenitor cells and bone marrow niche
Urao, N., & Ushio‐Fukai, M. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.10.532 · Cited by 170
“As described above, mice lacking essential components of the regulatory system that maintains ROS within the physiological levels, show accelerated HSCs senescence and progressive BM failure [17,20].”
BackgroundInfluentialShao, L., Feng, W., Li, H., Gardner, D., Luo, Y., Wang, Y., Liu, L., Meng, A., Sharpless, N. E., & Zhou, D. (2014) · Blood · doi:10.1182/blood-2013-07-515619 · Cited by 165
“Inactivation of the p16-Rb pathway restores the reproductive function of ATM HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.(20,21) These findings suggest that p16 plays a more significant role than Arf in regulating HSC self-renewal and inducing HSC senescence, even though both proteins are overex…”
BackgroundKim, H. M., Haraguchi, N., Ishii, H., Ohkuma, M., Okano, M., Mimori, K., Eguchi, H., Yamamoto, H., Nagano, H., Sekimoto, M., et al. (2011) · Annals of Surgical Oncology · doi:10.1245/s10434-011-2040-5 · Cited by 170
“It has been reported that the control of ROS is indispensable for hematopoietic stem cell maintenance.(31,32) In cancer, low ROS levels and radiation-resistance in breast a b”
BackgroundCurrent and potential therapeutic strategies for the treatment of ataxia-telangiectasia
Lavin, M. F., Gueven, N., Bottle, S. E., & Gatti, R. A. (2007) · British Medical Bulletin · doi:10.1093/bmb/ldm012 · Cited by 159
Fu, W., Liu, Y., & Yin, H. (2019) · Stem Cells International · doi:10.1155/2019/9757201 · Cited by 165
Asymmetric cancer cell division regulated by AKT
Dey‐Guha, I., Wolfer, A., Yeh, A. C., Albeck, J. G., Darp, R., Leon, E., Wulfkuhle, J. D., Petricoin, E. F., Wittner, B. S., & Ramaswamy, S. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109632108 · Cited by 157
NK Cells in Healthy Aging and Age-Associated Diseases
Camous, X., Pera, A., Solana, R., & Larbi, A. (2012) · BioMed Research International · doi:10.1155/2012/195956 · Cited by 154
“Hematopoietic stem cells (HSCs) become less and less able to renew the blood cells populations due to the shortening of telomeres and the accumulation of DNA lesions due to free radical created during their metabolism [21].”
BackgroundSato, A., Okada, M., Shibuya, K., Watanabe, E., Seino, S., Narita, Y., Shibui, S., Kayama, T., & Kitanaka, C. (2013) · Stem Cell Research · doi:10.1016/j.scr.2013.09.012 · Cited by 160
“…that the role of ROS in the control of stem cell self-renewal, for example, may be context-dependent, lending support to both ideas that ROS promote and inhibit self-renewal of stem cells (Ito et al., 2004, 2006; Kim and Wong, 2009; Le Belle et al., 2011; Smith et al., 2000; Yang et al., 2012).”
BackgroundHSC Niche Biology and HSC Expansion Ex Vivo
Kumar, S., & Geiger, H. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.07.003 · Cited by 174
“For example, ataxia telangiectasia mutated deficient (Atm / ) mice have shown progressive BM failure (HSC), as evidenced by failed BM reconstitution and a decline in hematocrit levels in old mice relative to young, which has been attributed to elevated ROS levels in HSCs [115], and which in addition lead to p38 activa…”
BackgroundHypoxia and Metabolic Properties of Hematopoietic Stem Cells
Zhang, C. C., & Sadek, H. A. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.5019 · Cited by 160
“By contrast, elevated levels of ROS decrease the self-renewal and quiescence of HSCs, as evidenced by the phenotypes of the ataxia telangiectasia mutated-deficient and Forkhead Box O (FOXO)-deficient HSCs (39, 80, 119, 133) [also see review ref.”
BackgroundJones, C. L., Sheth, A. I., & Jordan, C. T. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.02.013 · Cited by 166
Successful Treatment of Stevens-Johnson Syndrome with Steroid Pulse Therapy at Disease Onset
Araki, Y., Sotozono, C., Inatomi, T., Ueta, M., Yokoi, N., Ueda, E., Kishimoto, S., & Kinoshita, S. (2009) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2008.12.040 · Cited by 152
Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice
Farrés, J., Martín‐Caballero, J., Martínez, C. M., Lozano, J. J., Llacuna, L., Ampurdanés, C., Ruiz‐Herguido, C., Dantzer, F., Schreiber, V., Villunger, A., et al. (2013) · Blood · doi:10.1182/blood-2012-12-472845 · Cited by 159
The ATM–BID pathway regulates quiescence and survival of haematopoietic stem cells
Maryanovich, M., Oberkovitz, G., Niv, H., Vorobiyov, L., Zaltsman, Y., Brenner, O. J., Lapidot, T., Jung, S., & Gross, A. (2012) · Nature Cell Biology · doi:10.1038/ncb2468 · Cited by 159
The role of DNA damage repair in aging of adult stem cells
Kenyon, J. D., & Gerson, S. L. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm1064 · Cited by 152
p53, Stem Cells, and Reprogramming: Tumor Suppression beyond Guarding the Genome
Spike, B. T., & Wahl, G. M. (2011) · Genes & Cancer · doi:10.1177/1947601911410224 · Cited by 160
Structural basis and regulation of the reductive stress response
Manford, A. G., Mena, E. L., Shih, K. Y., Gee, C. L., McMinimy, R., Martínez-González, B., Sherriff, R., Lew, B., Zoltek, M., Rodríguez-Pérez, F., et al. (2021) · Cell · doi:10.1016/j.cell.2021.09.002 · Cited by 152
“If unmitigated, such oxidative stress exhausts stem cell populations, accelerates aging, and results in cancer or neurodegeneration (Corenblum et al., 2016; Ito et al., 2004; Papa et al., 2019; Suda et al., 2011).”
Ryoo, I.-G., Choi, B.-H., Ku, S., & Kwak, M. (2018) · Redox Biology · doi:10.1016/j.redox.2018.04.015 · Cited by 152
Kuo, M. T. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2095 · Cited by 151
“) mice with antioxidant NAC prolonged the survival (208).”
InfluentialFoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells
Yeo, H., Lyssiotis, C. A., Zhang, Y., Ying, H., Asara, J. M., Cantley, L. C., & Paik, J.-H. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.186 · Cited by 148
“Animal models of precocious stem-cell depletion or dysfunction consistently emphasize the role of key molecules involved in oxidative defense in maintaining stem-cell reserves: Atm (Ito et al , 2004), Tsc1 (Chen et al , 2008), Prdm16 (Chuikov et al , 2010), and FoxO3 (Miyamoto et al , 2007; Yalcin et al , 2008; Paik e…”
Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells
Jagušt, P., de Luxán‐Delgado, B., Parejo-Alonso, B., & Sancho, P. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00203 · Cited by 151
Immunosenescence: signaling pathways, diseases and therapeutic targets
Fu, Y., Wang, B., Alu, A., Hong, W., Hong, L., He, X., Shi, H., Cheng, P., & Yang, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02371-z · Cited by 168
“Interfering with the SNS nerves of adrenoreceptor β 3 (ADR β 3) signaling resulted in premature HSC aging in young mice, whereas stimulating ADR β 3 in older mice rejuvenated the functions of HSCs. 63 Zinc fi nger proteins in aged murine HSCs contribute to increased platelet bias and sustained myeloid HSC bias while su…”
InfluentialMitochondrial metabolism in hematopoietic stem cells requires functional FOXO3
Rimmelé, P., Liang, R. H.-S., Bigarella, C. L., Kocabaş, F., Xie, J., Serasinghe, M. N., Chipuk, J. E., Sadek, H. A., Zhang, C. C., & Ghaffari, S. (2015) · EMBO Reports · doi:10.15252/embr.201439704 · Cited by 146
“If this is correct, then why didn't the recipient irradiated mice also receive NAC preconditioning and throughout the reconstitution assay? Response: We were asking whether reduction of intrinsic ROS levels in LTHSC that are being transplanted will have an effect on their long term reconstitution after 16 weeks as has…”
InfluentialYalcin, S., Marinković, D., Mungamuri, S. K., Zhang, X., Tong, W., Sellers, R. S., & Ghaffari, S. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.292 · Cited by 150
“Excessive ROS concentrations lead to abnormal proliferation, growth and malignancies (Neumann et al , 2003; Ito et al , 2004).”
Autophagy in Stem Cell Maintenance and Differentiation
Vessoni, A. T., Muotri, A. R., & Okamoto, O. K. (2011) · Stem Cells and Development · doi:10.1089/scd.2011.0526 · Cited by 146
“It was also shown that intracellular ROS levels influence the long-term self-renewal capacity of hematopoietic stem cells (HSCs) [41,42].”
Oncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling
Gagné, L. M., Boulay, K., Topisirović, I., Huot, M., & Mallette, F. A. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.06.002 · Cited by 143
Novel Role of NADPH Oxidase in Angiogenesis and Stem/Progenitor Cell Function
Ushio‐Fukai, M., & Urao, N. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2582 · Cited by 141
“Hematopoietic stem cells from ATM-deficient mice show enhanced ROS levels and impaired stem cell functions, rescued by the treatment with the antioxidant N -acetyl- l -cysteine (97).”
Abbas, H. A., Macció, D. R., Coşkun, S., Jackson, J. G., Hazen, A. L., Sills, T., You, M. J., Hirschi, K. K., & Lozano, G. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.09.013 · Cited by 144
“Other studies have shown p16 activation resulting fromROS in bonemarrows (Ito et al., 2004; Liu et al., 2009b).”
BackgroundInfluentialSong, X., Ma, F., & Herrup, K. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0774-19.2019 · Cited by 133
“ATM has a known anti-oxidant function (Ito et al., 2004; Semlitsch et al., 2011) and can act as a redox sensor (Guo et al., 2010).”
BackgroundInherited myeloproliferative neoplasm risk affects haematopoietic stem cells
Bao, E. L., Nandakumar, S. K., Liao, X., Bick, A. G., Karjalainen, J. M., Tabaka, M., Gan, O. I., Havulinna, A. S., Kiiskinen, T., Lareau, C. A., et al. (2020) · Nature · doi:10.1038/s41586-020-2786-7 · Cited by 139
Energy Metabolism Plays a Critical Role in Stem Cell Maintenance and Differentiation
Hu, C., Fan, L., Cen, P., Chen, E., Jiang, Z., & Li, L. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17020253 · Cited by 143
“The balanced expression of regulatory proteins guarantees genomic stability through the cell cycle activation when stem cells respond to DNA damage or oxidative stress [20].”
BackgroundIonizing radiation and aging: rejuvenating an old idea
Richardson, R. B. (2009) · Aging · doi:10.18632/aging.100081 · Cited by 146
“Animals that lack the AT protein, which activates a cell-cycle checkpoint in response to oxidative stress, have reduced self-renewal of HSCs [139].”
BackgroundInfluential
Metadata
- Authors
- Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., Nomiyama, K., Hosokawa, K., Sakurada, K., Nakagata, N., Ikeda, Y., Mak, T. W., & Suda, T.
- Affiliations
- Keio University (JP)
- Kumamoto University (JP)
- University of Toronto (CA)
- Corresponding author
- Hirao, Atsushi
- Suda, Toshio
- ORCID
- Venue
- Nature
- Published
- 2004-10
- Volume
- 431
- Issue
- 7011
- Pages
- 997-1002
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2041897873
- Cited by
- 1,175
- References
- 30
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 38 · 2023: 31 · 2022: 37 · 2021: 51 · 2020: 44 · 2019: 58 · 2018: 47 · 2017: 59 · 2016: 73 · 2015: 71 · 2014: 75 · 2013: 88 · 2012: 77
- FWCI
- 25.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ATM, oxidative stress, hematopoietic stem cells, self-renewal, reactive oxygen species, ataxia telangiectasia, bone marrow failure, p16INK4a, retinoblastoma protein, DNA damage response, antioxidant therapy
- MeSH terms
- Acetylcysteine, Animals, Antioxidants, Cell Division, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Mice, Inbred C57BL, RNA, Messenger, Signal Transduction, Retinoblastoma Protein, Protein Serine-Threonine Kinases, Gene Deletion, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Cell Cycle Proteins, Cell Lineage, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Proteins, Mice, Ataxia Telangiectasia Mutated Proteins
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