Oxidative stress, bone marrow failure, and genome instability in hematopoietic stem cells

International Journal of Molecular Sciences

Volumn 16, Issue 2, 2015, Pages 2366-2385

  Richardson, Christine ^a   Yan, Shan ^a   Vestal, C Greer ^a  

^a UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE   (United States)

Author keywords

Aging; Base excision repair; Bone marrow failure; Cancer; Excision repair cross complement; Genome stability; Oxidative damage; Reactive oxygen species; ROS

Indexed keywords

REACTIVE OXYGEN METABOLITE; SUPEROXIDE DISMUTASE;

AGING; APOPTOSIS; BONE MARROW DEPRESSION; CELL DIFFERENTIATION; CELL FUNCTION; CELL PROLIFERATION; DEGENERATIVE DISEASE; DNA DAMAGE; DNA REPAIR; ENZYME ACTIVATION; FANCONI ANEMIA; GENOMIC INSTABILITY; HEMATOPOIETIC STEM CELL; HOMEOSTASIS AND REGULATION; HUMAN; INTRACELLULAR SIGNALING; NEOPLASM; NONHUMAN; OXIDATIVE STRESS; PHENOTYPE; REVIEW; ANIMAL; CYTOLOGY; METABOLISM; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PATHOLOGY;

ANIMALS; DNA DAMAGE; DNA REPAIR; GENOMIC INSTABILITY; HEMATOPOIETIC STEM CELLS; HEMOGLOBINURIA, PAROXYSMAL; HUMANS; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES;

EID: 84921883579     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms16022366     Document Type: Review

References (129)

1. Jackson, A.L.; Loeb, L.A. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat. Res. 2001, 477, 7-21.
2. Davies, K.J. Oxidative stress: The paradox of aerobic life. Biochem. Soc. Symp. 1995, 61, 1-31.
3. Beckman, K.B.; Ames, B.N. Oxidative decay of DNA. J. Biol. Chem. 1997, 272, 19633-19636.
4. Olinski, R.; Gackowski, D.; Foksinski, M.; Rozalski, R.; Roszkowski, K.; Jaruga, P. Oxidative DNA damage: Assessment of the role in carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome. Free Radic. Biol. Med. 2002, 33, 192-200.
5. Wang, M.C.; Bohmann, D.; Jasper, H. Jnk signaling confers tolerance to oxidative stress and extends lifespan in drosophila. Dev. Cell 2003, 5, 811-816.
6. Rossi, D.J.; Jamieson, C.H.; Weissman, I.L. Stems cells and the pathways to aging and cancer. Cell 2008, 132, 681-696.
7. Trushina, E.; McMurray, C.T. Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience 2007, 145, 1233-1248.
8. Er, T.K.; Tsai, S.M.; Wu, S.H.; Chiang, W.; Lin, H.C.; Lin, S.F.; Wu, S.H.; Tsai, L.Y.; Liu, T.Z. Antioxidant status and superoxide anion radical generation in acute myeloid leukemia. Clin. Biochem. 2007, 40, 1015-1019.
9. Li, L.; Li, M.; Sun, C.; Francisco, L.; Chakraborty, S.; Sabado, M.; McDonald, T.; Gyorffy, J.; Chang, K.; Wang, S.; et al. Altered hematopoietic cell gene expression precedes development of therapy-related myelodysplasia/acute myeloid leukemia and identifies patients at risk. Cancer Cell 2011, 20, 591-605.
10. Zhou, F.L.; Zhang, W.G.; Wei, Y.C.; Meng, S.; Bai, G.G.; Wang, B.Y.; Yang, H.Y.; Tian, W.; Meng, X.; Zhang, H.; et al. Involvement of oxidative stress in the relapse of acute myeloid leukemia. J. Biol. Chem. 2010, 285, 15010-15015.
11. Sies, H. Oxidative stress: Oxidants and antioxidants. Exp. Physiol. 1997, 82, 291-295.
12. Betteridge, D.J. What is oxidative stress? Metabolism 2000, 49, 3-8.
13. Jones, D.P. Redefining oxidative stress. Antioxid. Redox Signal. 2006, 8, 1865-1879.
14. De Bandeira, M.S.; da Fonseca, L.J.; da Guedes, S.G.; Rabelo, L.A.; Goulart, M.O.; Vasconcelos, S.M. Oxidative stress as an underlying contributor in the development of chronic complications in diabetes mellitus. Int. J. Mol. Sci. 2013, 14, 3265-3284.
15. Agnez-Lima, L.F.; Melo, J.T.; Silva, A.E.; Oliveira, A.H.; Timoteo, A.R.; Lima-Bessa, K.M.; Martinez, G.R.; Medeiros, M.H.; di Mascio, P.; Galhardo, R.S.; et al. DNA damage by singlet oxygen and cellular protective mechanisms. Mutat. Res. 2012, 751, 15-28.
16. Ames, B.N.; Shigenaga, M.K.; Hagen, T.M. Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA 1993, 90, 7915-7922.
17. Berquist, B.R.; Wilson, D.M., 3rd. Pathways for repairing and tolerating the spectrum of oxidative DNA lesions. Cancer Lett. 2012, 327, 61-72.
18. Riley, P.A. Free radicals in biology: Oxidative stress and the effects of ionizing radiation. Int. J. Radiat. Biol. 1994, 65, 27-33.
19. Dizdaroglu, M. Oxidatively induced DNA damage: Mechanisms, repair and disease. Cancer Lett. 2012, 327, 26-47.
20. Cook, J.A.; Gius, D.; Wink, D.A.; Krishna, M.C.; Russo, A.; Mitchell, J.B. Oxidative stress, redox, and the tumor microenvironment. Semin. Radiat. Oncol. 2004, 14, 259-266.
21. Lindahl, T. Instability and decay of the primary structure of DNA. Nature 1993, 362, 709-715.
22. Friedberg, E.C. DNA damage and repair. Nature 2003, 421, 436-440.
23. Ciccia, A.; Elledge, S.J. The DNA damage response: Making it safe to play with knives. Mol. Cell 2010, 40, 179-204.
24. Hoeijmakers, J.H. DNA damage, aging, and cancer. N. Engl. J. Med. 2009, 361, 1475-1485.
25. Cadet, J.; Ravanat, J.L.; TavernaPorro, M.; Menoni, H.; Angelov, D. Oxidatively generated complex DNA damage: Tandem and clustered lesions. Cancer Lett. 2012, 327, 5-15.
26. Gutowski, M.; Kowalczyk, S. A study of free radical chemistry: Their role and pathophysiological significance. Acta Biochim. Pol. 2013, 60, 1-16.
27. Rubattu, S.; Mennuni, S.; Testa, M.; Mennuni, M.; Pierelli, G.; Pagliaro, B.; Gabriele, E.; Coluccia, R.; Autore, C.; Volpe, M.; et al. Pathogenesis of chronic cardiorenal syndrome: Is there a role for oxidative stress? Int. J. Mol. Sci. 2013, 14, 23011-23032.
28. Yan, S.; Sorrell, M.; Berman, Z. Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress. Cell. Mol. Life Sci. CMLS 2014, 71, 3951-3967.
29. Barzilai, A.; Yamamoto, K. DNA damage responses to oxidative stress. DNA Repair (Amst) 2004, 3, 1109-1115.
30. Chen, B.P.; Li, M.; Asaithamby, A. New insights into the roles of ATM and DNA-PKCs in the cellular response to oxidative stress. Cancer Lett. 2012, 327, 103-110.
31. Cimprich, K.A.; Cortez, D. ATR: An essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 2008, 9, 616-627.
32. Jackson, S.P.; Bartek, J. The DNA-damage response in human biology and disease. Nature 2009, 461, 1071-1078.
33. Marechal, A.; Zou, L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol. 2013, doi:10.1101/cshperspect.a012716.
34. Branzei, D.; Foiani, M. Maintaining genome stability at the replication fork. Nat. Rev. Mol. Cell Biol. 2010, 11, 208-219.
35. Bakkenist, C.J.; Kastan, M.B. Initiating cellular stress responses. Cell 2004, 118, 9-17.
36. Bakkenist, C.J.; Kastan, M.B. DNA damage activates atm through intermolecular autophosphorylation and dimer dissociation. Nature 2003, 421, 499-506.
37. Guo, Z.; Kozlov, S.; Lavin, M.F.; Person, M.D.; Paull, T.T. ATM activation by oxidative stress. Science 2010, 330, 517-521.
38. Ambrose, M.; Gatti, R.A. Pathogenesis of ataxia-telangiectasia: The next generation of ATM functions. Blood 2013, 121, 4036-4045.
39. Bhatti, S.; Kozlov, S.; Farooqi, A.A.; Naqi, A.; Lavin, M.; Khanna, K.K. ATM protein kinase: The linchpin of cellular defenses to stress. Cell. Mol. Life Sci. CMLS 2011, 68, 2977-3006.
40. Ito, K.; Hirao, A.; Arai, F.; Takubo, K.; Matsuoka, S.; Miyamoto, K.; Ohmura, M.; Naka, K.; Hosokawa, K.; Ikeda, Y.; et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med. 2006, 12, 446-451.
41. Willis, J.; Patel, Y.; Lentz, B.L.; Yan, S. APE2 is required for ATR-chk1 checkpoint activation in response to oxidative stress. Proc. Natl. Acad. Sci. USA 2013, 110, 10592-10597.
42. Clerkin, J.S.; Naughton, R.; Quiney, C.; Cotter, T.G. Mechanisms of ros modulated cell survival during carcinogenesis. Cancer Lett. 2008, 266, 30-36.
43. Panayiotidis, M. Reactive oxygen species (ROS) in multistage carcinogenesis. Cancer Lett. 2008, 266, 3-5.
44. Sallmyr, A.; Fan, J.; Rassool, F.V. Genomic instability in myeloid malignancies: Increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair. Cancer Lett. 2008, 270, 1-9.
45. Przedborski, S.; Vila, M.; Jackson-Lewis, V. Neurodegeneration: What is it and where are we? J. Clin. Investig. 2003, 111, 3-10.
46. Radak, Z.; Zhao, Z.; Goto, S.; Koltai, E. Age-associated neurodegeneration and oxidative damage to lipids, proteins, and DNA. Mol. Asp. Med. 2011, 32, 305-315.
47. Rulten, S.L.; Caldecott, K.W. DNA strand break repair and neurodegeneration. DNA Repair 2013, 12, 558-567.
48. Rosenberg, P.S.; Tamary, H.; Alter, B.P. How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi anemia in the United States and Israel. Am. J. Med. Genet. A 2011, 155A, 1877-1883.
49. Alter, B.P.; Greene, M.H.; Velazquez, I.; Rosenberg, P.S. Cancer in Fanconi anemia. Blood 2003, 101, 2072.
50. Bakker, J.L.; van Mil, S.E.; Crossan, G.; Sabbaghian, N.; de Leeneer, K.; Poppe, B.; Adank, M.; Gille, H.; Verheul, H.; Meijers-Heijboer, H.; et al. Analysis of the novel Fanconi anemia gene SLX4/FancP in familial breast cancer cases. Hum. Mutat. 2013, 34, 70-73.
51. Cheng, N.C.; van de Vrugt, H.J.; van der Valk, M.A.; Oostra, A.B.; Krimpenfort, P.; de Vries, Y.; Joenje, H.; Berns, A.; Arwert, F. Mice with a targeted disruption of the Fanconi Anemia homolog FancA. Hum. Mol. Genet. 2000, 9, 1805-1811.
52. Hanna, L.A.; Foreman, R.K.; Tarasenko, I.A.; Kessler, D.S.; Labosky, P.A. Requirement for FoxD3 in maintaining pluripotent cells of the early mouse embryo. Genes Dev. 2002, 16, 2650-2661.
53. Sii-Felice, K.; Barroca, V.; Etienne, O.; Riou, L.; Hoffschir, F.; Fouchet, P.; Boussin, F.D.; Mouthon, M.A. Role of fanconi DNA repair pathway in neural stem cell homeostasis. Cell Cycle 2008, 7, 1911-1915.
54. Carreau, M. Not-so-novel phenotypes in the Fanconi anemia group D2 mouse model. Blood 2004, 103, 2430.
55. Aube, M.; Lafrance, M.; Charbonneau, C.; Goulet, I.; Carreau, M. Hematopoietic stem cells from FancC mice have lower growth and differentiation potential in response to growth factors. Stem Cells 2002, 20, 438-447.
56. Whitney, M.A.; Royle, G.; Low, M.J.; Kelly, M.A.; Axthelm, M.K.; Reifsteck, C.; Olson, S.; Braun, R.E.; Heinrich, M.C.; Rathbun, R.K.; et al. Germ cell defects and hematopoietic hypersensitivity to γ-interferon in mice with a targeted disruption of the Fanconi anemia c gene. Blood 1996, 88, 49-58.
57. Atanassov, B.S.; Barrett, J.C.; Davis, B.J. Homozygous germ line mutation in exon 27 of murine Brca2 disrupts the FancD2-Brca2 pathway in the homologous recombination-mediated DNA interstrand cross-links’ repair but does not affect meiosis. Genes Chromosomes Cancer 2005, 44, 429-437.
58. Navarro, S.; Meza, N.W.; Quintana-Bustamante, O.; Casado, J.A.; Jacome, A.; McAllister, K.; Puerto, S.; Surralles, J.; Segovia, J.C.; Bueren, J.A.; et al. Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1. Mol. Ther. 2006, 14, 525-535.
59. Houghtaling, S.; Timmers, C.; Noll, M.; Finegold, M.J.; Jones, S.N.; Meyn, M.S.; Grompe, M. Epithelial cancer in Fanconi anemia complementation group D2 (FancD2) knockout mice. Genes Dev. 2003, 17, 2021-2035.
60. Godthelp, B.C.; Wiegant, W.W.; Waisfisz, Q.; Medhurst, A.L.; Arwert, F.; Joenje, H.; Zdzienicka, M.Z. Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/Brca2. Mutat. Res. 2006, 594, 39-48.
61. Kumari, U.; Ya Jun, W.; Huat Bay, B.; Lyakhovich, A. Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in fanconi anemia cells. Oncogene 2014, 33, 165-172.
62. Zhang, X.; Li, J.; Sejas, D.P.; Pang, Q. Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells. Blood 2005, 106, 75-85.
63. Hadjur, S.; Ung, K.; Wadsworth, L.; Dimmick, J.; Rajcan-Separovic, E.; Scott, R.W.; Buchwald, M.; Jirik, F.R. Defective hematopoiesis and hepatic steatosis in mice with combined deficiencies of the genes encoding FancC and Cu/Zn superoxide dismutase. Blood 2001, 98, 1003-1011.
64. Langevin, F.; Crossan, G.P.; Rosado, I.V.; Arends, M.J.; Patel, K.J. FancD2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 2011, 475, 53-58.
65. Kraemer, K.H.; Patronas, N.J.; Schiffmann, R.; Brooks, B.P.; Tamura, D.; DiGiovanna, J.J. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: A complex genotype-phenotype relationship. Neuroscience 2007, 145, 1388-1396.
66. Van der Horst, G.T.; Meira, L.; Gorgels, T.G.; de Wit, J.; Velasco-Miguel, S.; Richardson, J.A.; Kamp, Y.; Vreeswijk, M.P.; Smit, B.; Bootsma, D.; et al. UVb radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice. DNA Repair (Amst) 2002, 1, 143-157.
67. De Waard, H.; de Wit, J.; Gorgels, T.G.; van den Aardweg, G.; Andressoo, J.O.; Vermeij, M.; van Steeg, H.; Hoeijmakers, J.H.; van der Horst, G.T. Cell type-specific hypersensitivity to oxidative damage in Csb and XPA mice. DNA Repair (Amst) 2003, 2, 13-25.
68. De Waard, H.; de Wit, J.; Andressoo, J.O.; van Oostrom, C.T.; Riis, B.; Weimann, A.; Poulsen, H.E.; van Steeg, H.; Hoeijmakers, J.H.; van der Horst, G.T.; et al. Different effects of Csa and Csb deficiency on sensitivity to oxidative DNA damage. Mol. Cell. Biol. 2004, 24, 7941-7948.
69. Spivak, G.; Hanawalt, P.C. Host cell reactivation of plasmids containing oxidative DNA lesions is defective in Cockayne syndrome but normal in UV-sensitive syndrome fibroblasts. DNA Repair (Amst) 2006, 5, 13-22.
70. D’Errico, M.; Parlanti, E.; Teson, M.; Degan, P.; Lemma, T.; Calcagnile, A.; Iavarone, I.; Jaruga, P.; Ropolo, M.; Pedrini, A.M.; et al. The role of Csa in the response to oxidative DNA damage in human cells. Oncogene 2007, 26, 4336-4343.
71. Melis, J.P.; van Steeg, H.; Luijten, M. Oxidative DNA damage and nucleotide excision repair. Antioxid. Redox Signal. 2013, 18, 2409-2419.
72. Hollander, M.C.; Philburn, R.T.; Patterson, A.D.; Velasco-Miguel, S.; Friedberg, E.C.; Linnoila, R.I.; Fornace, A.J., Jr. Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Proc. Natl. Acad. Sci. USA 2005, 102, 13200-13205.
73. Melis, J.P.; Wijnhoven, S.W.; Beems, R.B.; Roodbergen, M.; van den Berg, J.; Moon, H.; Friedberg, E.; van der Horst, G.T.; Hoeijmakers, J.H.; Vijg, J.; et al. Mouse models for xeroderma pigmentosum group a and group C show divergent cancer phenotypes. Cancer Res. 2008, 68, 1347-1353.
74. Fischer, J.L.; Kumar, M.A.; Day, T.W.; Hardy, T.M.; Hamilton, S.; Besch-Williford, C.; Safa, A.R.; Pollok, K.E.; Smith, M.L. The Xpc gene markedly affects cell survival in mouse bone marrow. Mutagenesis 2009, 24, 309-316.
75. Hayashi, M. Roles of oxidative stress in xeroderma pigmentosum. Adv. Exp. Med. Biol. 2008, 637, 120-127.
76. Walne, A.J.; Dokal, I. Advances in the understanding of dyskeratosis congenita. Br. J. Haematol. 2009, 145, 164-172.
77. Tummala, H.; Kirwan, M.; Walne, A.J.; Hossain, U.; Jackson, N.; Pondarre, C.; Plagnol, V.; Vulliamy, T.; Dokal, I. ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function. Am. J. Hum. Genet. 2014, 94, 246-256.
78. Zhou, D.; Shao, L.; Spitz, D.R. Reactive oxygen species in normal and tumor cells. Adv. Cancer Res. 2014, 122, 1-67.
79. Yahata, T.; Muguruma, Y.; Yumino, S.; Sheng, Y.; Uno, T.; Matsuzawa, H.; Ito, M.; Kato, S.; Hotta, T.; Ando, K.; et al. Quiescent human hematopoietic stem cells in the bone marrow niches organize the hierarchical structure of hematopoiesis. Stem Cells 2008, 26, 3228-3236.
80. Yahata, T.; Takanashi, T.; Muguruma, Y.; Ibrahim, A.A.; Matsuzawa, H.; Uno, T.; Sheng, Y.; Onizuka, M.; Ito, M.; Kato, S.; et al. Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood 2011, 118, 2941-2950.
81. Owusu-Ansah, E.; Banerjee, U. Reactive oxygen species prime drosophila haematopoietic progenitors for differentiation. Nature 2009, 461, 537-541.
82. Allen, R.G.; Tresini, M. Oxidative stress and gene regulation. Free Radic. Biol. Med. 2000, 28, 463-499.
83. Amundson, S.A.; Do, K.T.; Vinikoor, L.; Koch-Paiz, C.A.; Bittner, M.L.; Trent, J.M.; Meltzer, P.; Fornace, A.J., Jr. Stress-specific signatures: Expression profiling of p53 wild-type and -null human cells. Oncogene 2005, 24, 4572-4579.
84. Anantharam, V.; Lehrmann, E.; Kanthasamy, A.; Yang, Y.; Banerjee, P.; Becker, K.G.; Freed, W.J.; Kanthasamy, A.G. Microarray analysis of oxidative stress regulated genes in mesencephalic dopaminergic neuronal cells: Relevance to oxidative damage in Parkinson’s disease. Neurochem. Int. 2007, 50, 834-847.
85. Birrell, G.W.; Brown, J.A.; Wu, H.I.; Giaever, G.; Chu, A.M.; Davis, R.W.; Brown, J.M. Transcriptional response of saccharomyces cerevisiae to DNA-damaging agents does not identify the genes that protect against these agents. Proc. Natl. Acad. Sci. USA 2002, 99, 8778-8783.
86. Chuang, Y.Y., Chen, Y, Gadisetti, Chandramouli; V.R. Cook, J.A.; Coffin, D.; Tsai, M.H.; DeGraff, W.; Yan, H.;Zhao, S.; et al. Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002, 62, 6246-6254.
87. Islaih, M.; Halstead, B.W.; Kadura, I.A.; Li, B.; Reid-Hubbard, J.L.; Flick, L.; Altizer, J.L.; Thom Deahl, J.; Monteith, D.K.; Newton, R.K.; et al. Relationships between genomic, cell cycle, and mutagenic responses of TK6 cells exposed to DNA damaging chemicals. Mutat. Res. 2005, 578, 100-116.
88. Purdom-Dickinson, S.E.; Lin, Y.; Dedek, M.; Morrissy, S.; Johnson, J.; Chen, Q.M. Induction of antioxidant and detoxification response by oxidants in cardiomyocytes: Evidence from gene expression profiling and activation of Nrf2 transcription factor. J. Mol. Cell. Cardiol. 2007, 42, 159-176.
89. Weigel, A.L.; Handa, J.T.; Hjelmeland, L.M.Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic. Biol. Med. 2002, 33, 1419-1432.
90. Yu, Q.; He, M.; Lee, N.H.; Liu, E.T. Identification of Myc-mediated death response pathways by microarray analysis. J. Biol. Chem. 2002, 277, 13059-13066.
91. Zhang, Y.; Fong, C.C.; Wong, M.S.; Tzang, C.H.; Lai, W.P.; Fong, W.F.; Sui, S.F.; Yang, M. Molecular mechanisms of survival and apoptosis in Raw 264.7 macrophages under oxidative stress. Apoptosis 2005, 10, 545-556.
92. Abbas, H.A.; Maccio, D.R.; Coskun, S.; Jackson, J.G.; Hazen, A.L.; Sills, T.M.; You, M.J.; Hirschi, K.K.; Lozano, G. Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity. Cell Stem Cell 2010, 7, 606-617.
93. Wang, Y.; Zhou, Y.; Graves, D.T. FoxO transcription factors: Their clinical significance and regulation. BioMed Res. Int. 2014, doi:10.1155/2014/925350.
94. Miyamoto, K.; Araki, K.Y.; Naka, K.; Arai, F.; Takubo, K.; Yamazaki, S.; Matsuoka, S.; Miyamoto, T.; Ito, K.; Ohmura, M.; et al. FoxO3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007, 1, 101-112.
95. Tothova, Z.; Kollipara, R.; Huntly, B.J.; Lee, B.H.; Castrillon, D.H.; Cullen, D.E.; McDowell, E.P.; Lazo-Kallanian, S.; Williams, I.R.; Sears, C.; et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007, 128, 325-339.
96. Liu, X.; Greer, C.; Secombe, J. KDM5 interacts with foxO to modulate cellular levels ofoxidative stress. PLoS Genet. 2014, 10, e1004676.
97. Kocabas, F.; Zheng, J.; Thet, S.; Copeland, N.G.; Jenkins, N.A.; DeBerardinis, R.J.; Zhang, C.; Sadek, H.A. Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood 2012, 120, 4963-4972.
98. Mouzannar, R.; McCafferty, J.; Benedetto, G.; Richardson, C. Transcriptional and phospho-proteomic screens reveal stem cell activation of insulin-resistance and transformation pathways following a single minimally toxic episode of ROS. Int. J. Genomics Proteomics 2011, 2, 34-49.
99. Burdon, R.H. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic. Biol. Med. 1995, 18, 775-794.
100. Burdon, R.H.; Alliangana, D.; Gill, V. Hydrogen peroxide and the proliferation of BHK-21 cells. Free Radic. Res. 1995, 23, 471-486.
101. Francis, R.; Richardson, C. Multipotent hematopoietic cells susceptible to alternative double-strand break repair pathways that promote genome rearrangements. Genes Dev. 2007, 21, 1064-1074.
102. Shao, L.; Luo, Y.; Zhou, D. Hematopoietic stem cell injury induced by ionizing radiation. Antioxid. Redox Signal. 2014, 20, 1447-1462.
103. Wang, Y.; Liu, L.; Pazhanisamy, S.K.; Li, H.; Meng, A.; Zhou, D. Total body iradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells. Free Radic. Biol. Med. 2010, 48, 348-356.
104. Floratou, K.; Giannopoulou, E.; Antonacopoulou, A.; Karakantza, M.; Adonakis, G.; Kardamakis, D.; Matsouka, P. Oxidative stress due to radiation in CD34+ hematopoietic progenitor cells: Protection by IGF-1. J. Radiat. Res. 2012, 53, 672-685.
105. Yamaguchi, M.; Kashiwakura, I. Role of reactive oxygen species in the radiation response of human hematopoietic stem/progenitor cells. PLoS One 2013, 8, e70503.
106. Wang, B.; Li, W.; Liu, H.; Yang, L.; Liao, Q.; Cui, S.; Wang, H.; Zhao, L. miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition. Cell Death Dis. 2014, 5, e1335.
107. Saretzki, G.; Armstrong, L.; Leake, A.; Lako, M.; von Zglinicki, T. Stress defense in murine embryonic stem cells is superior to that of various differentiated murine cells. Stem Cells 2004, 22, 962-971.
108. Ergene, U.; Cagirgan, S.; Pehlivan, M.; Yilmaz, M.; Tombuloglu, M. Factors influencing engraftment in autologous peripheral hematopoetic stem cell transplantation (PBSCT). Transfus. Apher. Sci. 2007, 36, 23-29.
109. Rossi, D.J.; Bryder, D.; Seita, J.; Nussenzweig, A.; Hoeijmakers, J.; Weissman, I.L. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 2007, 447, 725-729.
110. Rossi, D.J.; Seita, J.; Czechowicz, A.; Bhattacharya, D.; Bryder, D.; Weissman, I.L. Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. Cell Cycle 2007, 6, 2371-2376.
111. Jang, Y.Y.; Sharkis, S.J. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 2007, 110, 3056-3063.
112. Beerman, I.; Seita, J.; Inlay, M.A.; Weissman, I.L.; Rossi, D.J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 2014, 15, 37-50.
113. Oh, J.; Lee, Y.D.; Wagers, A.J. Stem cell aging: Mechanisms, regulators and therapeutic opportunities. Nat. Med. 2014, 20, 870-880.
114. Urao, N.; Ushio-Fukai, M. Redox regulation of stem/progenitor cells and bone marrow niche. Free Radic. Biol. Med. 2013, 54, 26-39.
115. Ushio-Fukai, M.; Rehman, J. Redox and metabolic regulation of stem/progenitor cells and their niche. Antioxid. Redox Signal. 2014, 21, 1587-1590.
116. Picolli, C.; D’Aprile, A.; Ripoli, M.; Scrima, R.; Boffoli, D.; Tabilo, A.; Capitanio, N. The hypoxia-inducible factor is stabilized in circulating hematopoietic stem cells under normoxic conditions. FEBS Lett. 2007, 581, 3111-3119.
117. Picolli, C.; D’Aprile, A.; Ripoli, M.; Scrima, R.; Lecce, L.; Boffoli, D.; Tabilo, A; Capitanio, N. Bone-marrow derived hematopoietic stem/progenitor cells express multiple isoforms of NADPH oxidase and produce constituitively reactive oxygen species. Biochem. Biophys. Res. Commun. 2007, 353, 965-972.
118. Picolli, C.; Ria, R.; Ripoli, M.; Scrima, R.; Cela, O.; D’Aprile, A.; Boffoli, D.; Falzetti, F.; Tabilo, A; Capitanio, N, et al. Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells: Novel evidence of the occurrence of NAD(P)H oxidase activity. J. Biol. Chem. 2005, 280, 26467-26476.
119. Rouault-Pierre, K.; Lopez-Onieva, L.; Foster, K.; Anjos-Afonso, F.; Lamrissi-Garcia, I.; Serrano-Sanchez, M.; Mitter, R.; Ivanovic, Z.; de Verneuil, H.; Gribben, J, et al. HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell 2013, 13, 549-563.
120. Zhou, F.; Shen, Q.; Claret, F.X. Novel roles of reactive oxygen species in the pathogenesis of acute myeloid leukemia. J. Leukoc. Biol. 2013, 94, 423-429.
121. Hole, P.S.; Zabkiewicz, J.; Munje, C.; Newton, Z.; Pearn, L.; White, P.; Marquez, N.; Hills, R.K.; Burnett, A.K.; Tonks, A, et al. Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling. Blood 2013, 122, 3322-3330.
122. Juntilla, M.M.; Patil, V.D.; Calamito, M.; Joshi, R.P.; Birnbaum, M.J.; Koretzky, G.A. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 2010, 115, 4030-4038.
123. Woolley, J.F.; Naughton, R.; Stanicka, J.; Gough, D.R.; Bhatt, L.; Dickinson, B.C.; Chang, C.J.; Cotter, T.G. H2O2 production downstream of FLT3 is mediated by p22phox in the endoplasmic reticulum and is required for STAT5 signalling. PLoS One 2012, 7, e34050.
124. Sallmyr, A.; Fan, J.; Datta, K.; Kim, K.T.; Grosu, D.; Shapiro, P.; Small, D.; Rassool, F. Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ros production, DNA damage, and misrepair: Implications for poor prognosis in AML. Blood 2008, 111, 3173-3182.
125. He, L.; Luo, L.; Proctor, S.J.; Middleton, P.G.; Blakely, E.L.; Taylor, R.W.; Turnbull, D.M. Somatic mitochondrial DNA mutations in adult-onset leukaemia. Leukemia 2003, 17, 2487-2491.
126. Hasselbalch, H.C.; Thomassen, M.; Hasselbalch Riley, C.; Kjaer, L.; Stauffer Larsen, T.; Jensen, M.K.; Bjerrum, O.W.; Kruse, T.A.; Skov, V. Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms: Potential implications of downregulation of Nrf2 for genomic instability and disease progression. PLoS One 2014, 9, e112786.
127. Rushworth, S.A.; MacEwan, D.J. HO-1 underlies resistance of aml cells to TNF-induced apoptosis. Blood 2008, 111, 3793-3801.
128. Chung, Y.J.; Robert, C.; Gough, S.M.; Rassool, F.V.; Aplan, P.D. Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome. Leuk. Res. 2014, 38, 95-102.
129. Vadukoot, A.K.; AbdulSalam, S.F.; Wunderlich, M.; Pullen, E.D.; Landero-Figueroa, J.; Mulloy, J.C.; Merino, E.J. Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells. Bioorg. Med. Chem. 2014, 22, 6885-6892.