International Journal of Hematology

, Volume 93, Issue 4, pp 434–439 | Cite as

Maintenance of genomic integrity in hematopoietic stem cells

Progress in Hematology Fanconi anemia and mechanisms of the DNA damage response


Hematopoietic stem cells (HSCs) maintain hematopoietic homeostasis throughout a mammal’s lifespan through self-renewal and differentiation into mature blood cells. Within a bone marrow niche, HSCs adopt a quiescent state and remain in the non-dividing, G0 phase of the cell cycle. It was recently shown that maintenance of genomic integrity is crucial for the preservation of self-renewal capacity of HSCs. In this review, we focus on progress in elucidating the roles of reactive oxygen species (ROS) and DNA damage responses (DDR) in maintaining genomic integrity, and thus HSC function. Several studies have demonstrated that inappropriate ROS levels arising from disruption of the Atm, PI3K-Akt, or Mdm2-p53 pathways impair HSC function in vivo. Intriguing evidence that stem cells use specific DDR mechanisms is also accumulating. Although murine HSCs are more resistant than progenitor cells to mild DNA damage in vivo, the surviving HSCs frequently acquire genetic aberrations that can lead to leukemogenesis. Indeed, non-dividing HSCs employ the error-prone non-homologous end-joining pathway of DNA repair to fix DNA breaks, whereas progenitors undergo apoptosis; proliferating HSCs employ the high-fidelity homologous recombination mechanism. Dissection of HSC-specific mechanisms for the maintenance of genomic integrity may provide valuable insights into the biology of both HSCs and leukemia stem cells.


Hematopoietic stem cells (HSCs) Reactive oxygen species (ROS) DNA damage response (DDR) Non-homologous end-joining (NHEJ) 


  1. 1.
    Arai F, Hirao A, Suda T. Regulation of hematopoiesis and its interaction with stem cell niches. Int J Hematol. 2005;82(5):371–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Kiel MJ, Morrison SJ. Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol. 2008;8(4):290–301.PubMedCrossRefGoogle Scholar
  3. 3.
    Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA. 1994;91(21):9857–60.PubMedCrossRefGoogle Scholar
  4. 4.
    Samper E, Fernandez P, Eguia R, et al. Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood. 2002;99(8):2767–75.PubMedCrossRefGoogle Scholar
  5. 5.
    Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood. 2003;102(2):517–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Parmar K, Kim J, Sykes SM, et al. Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells. 2010;28(7):1186–95.PubMedCrossRefGoogle Scholar
  7. 7.
    Zhang QS, Marquez-Loza L, Eaton L, et al. Fancd2 / mice have hematopoietic defects that can be partially corrected by resveratrol. Blood. 2010;116(24):5140–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Takubo K, Goda N, Yamada W, et al. Regulation of the HIF-1α level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391–402.PubMedCrossRefGoogle Scholar
  9. 9.
    Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood. 2007;110(8):3056–63.PubMedCrossRefGoogle Scholar
  10. 10.
    Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12(4):446–51.PubMedCrossRefGoogle Scholar
  11. 11.
    Ito K, Hirao A, Arai F, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431(7011):997–1002.PubMedCrossRefGoogle Scholar
  12. 12.
    Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24(50):7410–25.PubMedCrossRefGoogle Scholar
  13. 13.
    Yamazaki S, Iwama A, Takayanagi S, et al. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J. 2006;25(15):3515–23.PubMedCrossRefGoogle Scholar
  14. 14.
    Tothova Z, Kollipara R, Huntly BJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325–39.PubMedCrossRefGoogle Scholar
  15. 15.
    Miyamoto K, Araki KY, Naka K, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007;1(1):101–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Yalcin S, Zhang X, Luciano JP, et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J Biol Chem. 2008;283(37):25692–705.PubMedCrossRefGoogle Scholar
  17. 17.
    Naka K, Hoshii T, Muraguchi T, et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463(7281):676–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Gan B, Sahin E, Jiang S, et al. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc Natl Acad Sci USA. 2008;105(49):19384–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Zheng P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008;205(10):2397–408.PubMedCrossRefGoogle Scholar
  20. 20.
    Lee JY, Nakada D, Yilmaz OH, et al. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell. 2010;7(5):593–605.PubMedCrossRefGoogle Scholar
  21. 21.
    Abbas HA, Maccio DR, Coskun S, et al. Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity. Cell Stem Cell. 2010;7(5):606–17.PubMedCrossRefGoogle Scholar
  22. 22.
    Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447(7145):725–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Nijnik A, Woodbine L, Marchetti C, et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007;447(7145):686–90.PubMedCrossRefGoogle Scholar
  24. 24.
    Milyavsky M, Gan OI, Trottier M, et al. A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell. 2010;7(2):186–97.PubMedCrossRefGoogle Scholar
  25. 25.
    Mohrin M, Bourke E, Alexander D, et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell. 2010;7(2):174–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Branzei D, Foiani M. Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 2008;9(4):297–308.PubMedCrossRefGoogle Scholar
  27. 27.
    Bondar T, Medzhitov R. p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell. 2010;6(4):309–22.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2011

Authors and Affiliations

  1. 1.Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research InstituteKanazawa UniversityKanazawaJapan

Personalised recommendations