Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover

Leukemia volume 20, pages 1706–1716 (2006)Cite this article

Abstract

Telomeres both reflect and limit the replicative lifespan of normal somatic cells. Immature sub-populations of human CD34+38− hematopoietic stem cell (HSC) can be identified in vitro based on their growth kinetics and telomere length. Fluorescence in situ hybridization and flow cytometry (flow-FISH) has been used to characterize telomere length dynamics as a surrogate marker for HSC turnover in vivo. Investigations in normal steady-state hematopoiesis provided the basis for follow-up studies in model scenarios characterized by increased HSC turnover. Disorders with underlying malignant transformation of HSC (e.g., chronic myeloid leukemia (CML)) can be discriminated from disease states with increased HSC turnover rates secondary to depletion of the stem cell compartment, for example, as in defined bone marrow failure syndromes. In some of these model scenarios, the degree of telomere shortening can be correlated with disease duration, disease stage and severity as well as with response to disease-modifying treatment strategies. Whether increased telomere shortening represents a causal link between HSC turnover, replicative senescence and/or the induction of genetic instability in acquired HSC disorders remains to be shown. However, data from congenital disorders, like dyskeratosis congenita (DKC), suggest that disturbed telomere maintenance may play a role for replicative exhaustion of the HSC pool in vivo.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Blackburn EH . The end of the (DNA) line. Nat Struct Biol 2000; 7: 847–850.

    Article  CAS  PubMed  Google Scholar 

  2. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H et al. Mammalian telomeres end in a large duplex loop. Cell 1999; 97: 503–514.

    Article  CAS  PubMed  Google Scholar 

  3. Smogorzewska A, de LT . Regulation of telomerase by telomeric proteins. Annu Rev Biochem 2004; 73: 177–208.

    Article  CAS  PubMed  Google Scholar 

  4. Greider CW . Telomere length regulation. Annu Rev Biochem 1996; 65: 337–365.

    Article  CAS  PubMed  Google Scholar 

  5. Hande MP, Samper E, Lansdorp P, Blasco MA . Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J Cell Biol 1999; 144: 589–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. de Lange T . Telomere dynamics and genome instability in human cancer. In: Blackburn EH, Greider C (eds) Telomeres Plainview. Cold Spring Harbour Laboratory Press: NY, 1995, pp 265–293.

    Google Scholar 

  7. Watson JD . Origin of concatemeric T7 DNA. Nat New Biol 1972; 239: 197–201.

    Article  CAS  PubMed  Google Scholar 

  8. Olovnikov AM . A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 1973; 41: 181–190.

    Article  CAS  PubMed  Google Scholar 

  9. Harley CB, Futcher AB, Greider CW . Telomeres shorten during ageing of human fibroblasts. Nature 1990; 345: 458–460.

    Article  CAS  PubMed  Google Scholar 

  10. Blasco MA . Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 2005; 6: 611–622.

    Article  CAS  PubMed  Google Scholar 

  11. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC . Telomere reduction in human colorectal carcinoma and with ageing. Nature 1990; 346: 866–868.

    Article  CAS  PubMed  Google Scholar 

  12. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 1992; 89: 10114–10118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Harley CB, Vaziri H, Counter CM, Allsopp RC . The telomere hypothesis of cellular aging. Exp Gerontol 1992; 27: 375–382.

    Article  CAS  PubMed  Google Scholar 

  14. Blackburn EH . Telomerases. Annu Rev Biochem 1992; 61: 113–129.

    Article  CAS  PubMed  Google Scholar 

  15. Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW . Telomerase activity in human germline and embryonic tissues and cells. Dev Genet 1996; 18: 173–179.

    Article  CAS  PubMed  Google Scholar 

  16. Hayflick L . The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37: 614–636.

    Article  CAS  PubMed  Google Scholar 

  17. Shay JW, Bacchetti S . A survey of telomerase activity in human cancer. Eur J Cancer 1997; 33: 787–791.

    Article  CAS  PubMed  Google Scholar 

  18. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266: 2011–2015.

    Article  CAS  PubMed  Google Scholar 

  19. Blasco MA, Hahn WC . Evolving views of telomerase and cancer. Trends Cell Biol 2003; 13: 289–294.

    Article  CAS  PubMed  Google Scholar 

  20. Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR . Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 1997; 276: 561–567.

    Article  CAS  PubMed  Google Scholar 

  21. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997; 90: 785–795.

    Article  CAS  PubMed  Google Scholar 

  22. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 1997; 277: 955–959.

    Article  CAS  PubMed  Google Scholar 

  23. Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP et al. The RNA component of human telomerase. Science 1995; 269: 1236–1241.

    Article  CAS  PubMed  Google Scholar 

  24. Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet 1997; 17: 498–502.

    Article  CAS  PubMed  Google Scholar 

  25. Counter CM, Meyerson M, Eaton EN, Ellisen LW, Caddle SD, Haber DA et al. Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase. Oncogene 1998; 16: 1217–1222.

    Article  CAS  PubMed  Google Scholar 

  26. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998; 279: 349–352.

    Article  CAS  PubMed  Google Scholar 

  27. Vaziri H, Benchimol S . Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol 1998; 8: 279–282.

    Article  CAS  PubMed  Google Scholar 

  28. Wege H, Le HT, Chui MS, Liu L, Wu J, Giri R et al. Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential. Gastroenterology 2003; 124: 432–444.

    Article  CAS  PubMed  Google Scholar 

  29. Wege H, Chui MS, Le HT, Strom SC, Zern MA . In vitro expansion of human hepatocytes is restricted by telomere-dependent replicative aging. Cell Transplant 2003; 12: 897–906.

    Article  PubMed  Google Scholar 

  30. Morales CP, Holt SE, Ouellette M, Kaur KJ, Yan Y, Wilson KS et al. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat Genet 1999; 21: 115–118.

    Article  CAS  PubMed  Google Scholar 

  31. Jiang XR, Jimenez G, Chang E, Frolkis M, Kusler B, Sage M et al. Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype. Nat Genet 1999; 21: 111–114.

    Article  CAS  PubMed  Google Scholar 

  32. Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA . Creation of human tumour cells with defined genetic elements. Nature 1999; 400: 464–468.

    Article  CAS  PubMed  Google Scholar 

  33. Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A et al. Inhibition of telomerase limits the growth of human cancer cells. Nat Med 1999; 5: 1164–1170.

    Article  CAS  PubMed  Google Scholar 

  34. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997; 91: 25–34.

    Article  CAS  PubMed  Google Scholar 

  35. Lee HW, Blasco MA, Gottlieb GJ, Horner JW, Greider CW, DePinho RA . Essential role of mouse telomerase in highly proliferative organs. Nature 1998; 392: 569–574.

    Article  CAS  PubMed  Google Scholar 

  36. Lansdorp PM . Self-renewal of stem cells. Biol Blood Marrow Transplant 1997; 3: 171–178.

    CAS  PubMed  Google Scholar 

  37. Till JE, McCulloch EA . A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961; 14: 213–222.

    Article  CAS  PubMed  Google Scholar 

  38. Moore MA, Williams N, Metcalf D . In vitro colony formation by normal and leukemic human hematopoietic cells: characterization of the colony-forming cells. J Natl Cancer Inst 1973; 50: 603–623.

    Article  CAS  PubMed  Google Scholar 

  39. Brummendorf TH, Dragowska W, Zijlmans JMJM, Thornbury G, Lansdorp PM . Asymmetric cell divisions sustain long-term hematopoiesis from single-sorted human fetal liver cells. J Exp Med 1998; 188: 1117–1124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Suda T, Suda J, Ogawa M . Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. Proc Natl Acad Sci USA 1984; 81: 2520–2524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Denkers IA, Dragowska W, Jaggi B, Palcic B, Lansdorp PM . Time lapse video recordings of highly purified human hematopoietic progenitor cells in culture. Stem Cells 1993; 11: 243–248.

    Article  CAS  PubMed  Google Scholar 

  42. Mayani H, Dragowska W, Lansdorp PM . Lineage commitment in human hemopoiesis involves asymmetric cell division of multipotent progenitors and does not appear to be influenced by cytokines. J Cell Physiol 1993; 157: 579–586.

    Article  CAS  PubMed  Google Scholar 

  43. Huang S, Law P, Francis K, Palsson BO, Ho AD . Symmetry of initial cell divisions among primitive hematopoietic progenitors is independent of ontogenic age and regulatory molecules. Blood 1999; 94: 2595–2604.

    CAS  PubMed  Google Scholar 

  44. Lansdorp PM, Dragowska W, Mayani H . Ontogeny-related changes in proliferative potential of human hematopoietic cells. J Exp Med 1993; 178: 787–791.

    Article  CAS  PubMed  Google Scholar 

  45. Lansdorp PM . Developmental changes in the function of hematopoietic stem cells. Exp Hematol 1995; 23: 187–191.

    CAS  PubMed  Google Scholar 

  46. 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: 9857–9860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lansdorp PM, Poon S, Chavez E, Dragowska V, Zijlmans M, Bryan T et al. Telomeres in the haemopoietic system. Ciba Found Symp 1997; 211: 209–218; discussion 219–222.

    CAS  PubMed  Google Scholar 

  48. Broccoli D, Young JW, de Lange T . Telomerase activity in normal and malignant hematopoietic cells. Proc Natl Acad Sci USA 1995; 92: 9082–9086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chiu CP, Dragowska W, Kim NW, Vaziri H, Yui J, Thomas TE et al. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells 1996; 14: 239–248.

    Article  CAS  PubMed  Google Scholar 

  50. Yui J, Chiu CP, Lansdorp PM . Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood 1998; 91: 3255–3262.

    CAS  PubMed  Google Scholar 

  51. Gammaitoni L, Weisel KC, Gunetti M, Wu KD, Bruno S, Pinelli S et al. Elevated telomerase activity and minimal telomere loss in cord blood long-term cultures with extensive stem cell replication. Blood 2004; 103: 4440–4448.

    Article  CAS  PubMed  Google Scholar 

  52. Allsopp RC, Morin GB, Horner JW, DePinho R, Harley CB, Weissman IL . Effect of TERT over-expression on the long-term transplantation capacity of hematopoietic stem cells. Nat Med 2003; 9: 369–371.

    Article  CAS  PubMed  Google Scholar 

  53. Zimmermann S, Glaser S, Ketteler R, Waller CF, Klingmuller U, Martens UM . Effects of telomerase modulation in human hematopoietic progenitor cells. Stem Cells 2004; 22: 741–749.

    Article  CAS  PubMed  Google Scholar 

  54. Elwood NJ, Jiang XR, Chiu CP, Lebkowski JS, Smith CA . Enhanced long-term survival, but no increase in replicative capacity, following retroviral transduction of human cord blood CD34+ cells with human telomerase reverse transcriptase. Haematologica 2004; 89: 377–378.

    PubMed  Google Scholar 

  55. Wang JC, Warner JK, Erdmann N, Lansdorp PM, Harrington L, Dick JE . Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells. Proc Natl Acad Sci USA 2005; 102: 14398–14403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Martens UM, Chavez EA, Poon SS, Schmoor C, Lansdorp PM . Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp Cell Res 2000; 256: 291–299.

    Article  CAS  PubMed  Google Scholar 

  57. Bartolovic K, Balabanov S, Berner B, Buhring HJ, Komor M, Becker S et al. Clonal heterogeneity in growth kinetics of CD34+CD38− human cord blood cells in vitro is correlated with gene expression pattern and telomere length. Stem Cells 2005; 23: 946–957.

    Article  CAS  PubMed  Google Scholar 

  58. Van Ziffle JA, Baerlocher GM, Lansdorp PM . Telomere length in subpopulations of human hematopoietic cells. Stem Cells 2003; 21: 654–660.

    Article  CAS  PubMed  Google Scholar 

  59. Sakoff JA, De WE, Garg MB, Denham J, Scorgie FE, Enno A et al. Telomere length in haemopoietic stem cells can be determined from that of mononuclear blood cells or whole blood. Leukemia Lymphoma 2002; 43: 2017–2020.

    Article  PubMed  Google Scholar 

  60. Rufer N, Dragowska W, Thornbury G, Roosnek E, Lansdorp PM . Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat Biotechnol 1998; 16: 743–747.

    Article  CAS  PubMed  Google Scholar 

  61. Weng NP, Levine BL, June CH, Hodes RJ . Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc Natl Acad Sci USA 1995; 92: 11091–11094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Weng NP, Granger L, Hodes RJ . Telomere lengthening and telomerase activation during human B cell differentiation. Proc Natl Acad Sci USA 1997; 94: 10827–10832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rufer N, Brummendorf TH, Kolvraa S, Bischoff C, Christensen K, Wadsworth L et al. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med 1999; 190: 157–167.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Martens UM, Brass V, Sedlacek L, Pantic M, Exner C, Guo Y et al. Telomere maintenance in human B lymphocytes. Br J Haematol 2002; 119: 810–818.

    Article  CAS  PubMed  Google Scholar 

  65. Slagboom PE, Droog S, Boomsma DI . Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet 1994; 55: 876–882.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Andrew T, Aviv A, Falchi M, Surdulescu GL, Gardner JP, Lu X et al. Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs. Am J Hum Genet 2006; 78: 480–486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kipling D, Cooke HJ . Hypervariable ultra-long telomeres in mice. Nature 1990; 347: 400–402.

    Article  CAS  PubMed  Google Scholar 

  68. Martens UM, Zijlmans JM, Poon SS, Dragowska W, Yui J, Chavez EA et al. Short telomeres on human chromosome 17p. Nat Genet 1998; 18: 76–80.

    Article  CAS  PubMed  Google Scholar 

  69. Herrera E, Samper E, Martin-Caballero J, Flores JM, Lee HW, Blasco MA . Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J 1999; 18: 2950–2960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Herrera E, Martinez A, Blasco MA . Impaired germinal center reaction in mice with short telomeres. EMBO J 2000; 19: 472–481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL . Telomerase is required to slow telomere shortening and extend replicative lifespan of HSC during serial transplantation. Blood 2003; 102: 517–520.

    Article  CAS  PubMed  Google Scholar 

  72. Allsopp RC, Cheshier S, Weissman IL . Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J Exp Med 2001; 193: 917–924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wright WE, Shay JW . Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nat Med 2000; 6: 849–851.

    Article  CAS  PubMed  Google Scholar 

  74. Awaya N, Baerlocher GM, Manley TJ, Sanders JE, Mielcarek M, Torok-Storb B et al. Telomere shortening in hematopoietic stem cell transplantation: a potential mechanism for late graft failure? Biol Blood Marrow Transplant 2002; 8: 597–600.

    Article  PubMed  Google Scholar 

  75. Damm K, Hemmann U, Garin-Chesa P, Hauel N, Kauffmann I, Priepke H et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J 2001; 20: 6958–6968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pascolo E, Wenz C, Lingner J, Hauel N, Priepke H, Kauffmann I et al. Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate. J Biol Chem 2002; 277: 15566–15572.

    Article  CAS  PubMed  Google Scholar 

  77. Abkowitz JL, Persik MT, Shelton GH, Ott RL, Kiklevich JV, Catlin SN et al. Behavior of hematopoietic stem cells in a large animal. Proc Natl Acad Sci USA 1995; 92: 2031–2035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Brummendorf TH, Mak J, Sabo KM, Baerlocher GM, Dietz K, Abkowitz JL et al. Longitudinal studies of telomere length in feline blood cells: implications for hematopoietic stem cell turnover in vivo. Exp Hematol 2002; 30: 1147–1152.

    Article  PubMed  Google Scholar 

  79. Lindsey J, McGill NI, Lindsey LA, Green DK, Cooke HJ . In vivo loss of telomeric repeats with age in humans. Mutat Res 1991; 256: 45–48.

    Article  CAS  PubMed  Google Scholar 

  80. Yamada O, Oshimi K, Motoji T, Mizoguchi H . Telomeric DNA in normal and leukemic blood cells. J Clin Invest 1995; 95: 1117–1123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Iwama H, Ohyashiki K, Ohyashiki JH, Hayashi S, Yahata N, Ando K et al. Telomeric length and telomerase activity vary with age in peripheral blood cells obtained from normal individuals. Hum Genet 1998; 102: 397–402.

    Article  CAS  PubMed  Google Scholar 

  82. Ball SE, Gibson FM, Rizzo S, Tooze JA, Marsh JC, Gordon-Smith EC . Progressive telomere shortening in aplastic anemia. Blood 1998; 91: 3582–3592.

    CAS  PubMed  Google Scholar 

  83. Frenck RW, Blackburn EH, Shannon KM . The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci USA 1998; 95: 5607–5610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF et al. Obesity, cigarette smoking, and telomere length in women. Lancet 2005; 366: 662–664.

    Article  CAS  PubMed  Google Scholar 

  85. Zeichner SL, Palumbo P, Feng Y, Xiao X, Gee D, Sleasman J et al. Rapid telomere shortening in children. Blood 1999; 93: 2824–2830.

    CAS  PubMed  Google Scholar 

  86. von Zglinicki T . Role of oxidative stress in telomere length regulation and replicative senescence. Ann NY Acad Sci 2000; 908: 99–110.

    Article  CAS  PubMed  Google Scholar 

  87. Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA . Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361: 393–395.

    Article  CAS  PubMed  Google Scholar 

  88. Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA 2004; 101: 17312–17315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Baerlocher GM, Mak J, Roth A, Rice KS, Lansdorp PM . Telomere shortening in leukocyte subpopulations from baboons. J Leukocyte Biol 2003; 73: 289–296.

    Article  CAS  PubMed  Google Scholar 

  90. Shepherd BE, Guttorp P, Lansdorp PM, Abkowitz JL . Estimating human hematopoietic stem cell kinetics using granulocyte telomere lengths. Exp Hematol 2004; 32: 1040–1050.

    Article  CAS  PubMed  Google Scholar 

  91. Mackey MC . Cell kinetic status of haematopoietic stem cells. Cell Prolif 2001; 34: 71–83.

    Article  CAS  PubMed  Google Scholar 

  92. Scheding S, Ersoez I, Hartmann U, Bartolovic K, Balabanov S, Salama A et al. Peripheral blood telomere length measurements indicate that hematopoietic stem cell turnover is not significantly increased in whole blood and apheresis platelets donors. Transfusion 2003; 43: 1089–1095.

    Article  PubMed  Google Scholar 

  93. Wynn RF, Cross MA, Hatton C, Will AM, Lashford LS, Dexter TM et al. Accelerated telomere shortening in young recipients of allogeneic bone-marrow transplants. Lancet 1998; 351: 178–181.

    Article  CAS  PubMed  Google Scholar 

  94. Lee J, Kook H, Chung I, Kim H, Park M, Kim C et al. Telomere length changes in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 1999; 24: 411–415.

    Article  CAS  PubMed  Google Scholar 

  95. de Pauw ES, Otto SA, Wijnen JT, Vossen JM, van Weel MH, Tanke HJ et al. Long-term follow-up of recipients of allogeneic bone marrow grafts reveals no progressive telomere shortening and provides no evidence for haematopoietic stem cell exhaustion. Br J Haematol 2002; 116: 491–496.

    Article  PubMed  Google Scholar 

  96. Roelofs H, de Pauw ES, Zwinderman AH, Opdam SM, Willemze R, Tanke HJ et al. Homeostasis of telomere length rather than telomere shortening after allogeneic peripheral blood stem cell transplantation. Blood 2003; 101: 358–362.

    Article  CAS  PubMed  Google Scholar 

  97. Notaro R, Cimmino A, Tabarini D, Rotoli B, Luzzatto L . In vivo telomere dynamics of human hematopoietic stem cells. Proc Natl Acad Sci USA 1997; 94: 13782–13785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rufer N, Brummendorf TH, Chapuis B, Helg C, Lansdorp PM, Roosnek E . Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation. Blood 2001; 97: 575–577.

    Article  CAS  PubMed  Google Scholar 

  99. Robertson JD, Testa NG, Russell NH, Jackson G, Parker AN, Milligan DW et al. Accelerated telomere shortening following allogeneic transplantation is independent of the cell source and occurs within the first year post transplant. Bone Marrow Transplant 2001; 27: 1283–1286.

    Article  CAS  PubMed  Google Scholar 

  100. Mathioudakis G, Storb R, McSweeney PA, Torok-Storb B, Lansdorp PM, Brummendorf TH et al. Polyclonal hematopoiesis with variable telomere shortening in human long-term allogeneic marrow graft recipients. Blood 2000; 96: 3991–3994.

    CAS  PubMed  Google Scholar 

  101. Wynn R, Thornley I, Freedman M, Saunders EF . Telomere shortening in leucocyte subsets of long-term survivors of allogeneic bone marrow transplantation. Br J Haematol 1999; 105: 997–1001.

    Article  CAS  PubMed  Google Scholar 

  102. Lahav M, Uziel O, Kestenbaum M, Fraser A, Shapiro H, Radnay J et al. Nonmyeloablative conditioning does not prevent telomere shortening after allogeneic stem cell transplantation. Transplantation 2005; 80: 969–976.

    Article  PubMed  Google Scholar 

  103. Thornley I, Sutherland R, Wynn R, Nayar R, Sung L, Corpus G et al. Early hematopoietic reconstitution after clinical stem cell transplantation: evidence for stochastic stem cell behavior and limited acceleration in telomere loss. Blood 2002; 99: 2387–2396.

    Article  CAS  PubMed  Google Scholar 

  104. Widmann TA, Willmann B, Pfreundschuh M, Beelen DW . Influence of telomere length on short-term recovery after allogeneic stem cell transplantation. Exp Hematol 2005; 33: 1257–1261.

    Article  PubMed  Google Scholar 

  105. Brummendorf TH, Rufer N, Baerlocher GM, Roosnek E, Lansdorp PM . Limited telomere shortening in hematopoietic stem cells after transplantation. Ann NY Acad Sci 2001; 938: 1–7.

    Article  CAS  PubMed  Google Scholar 

  106. Akiyama M, Hoshi Y, Sakurai S, Yamada H, Yamada O, Mizoguchi H . Changes of telomere length in children after hematopoietic stem cell transplantation. Bone Marrow Transplant 1998; 21: 167–171.

    Article  CAS  PubMed  Google Scholar 

  107. Akiyama M, Asai O, Kuraishi Y, Urashima M, Hoshi Y, Sakamaki H et al. Shortening of telomeres in recipients of both autologous and allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2000; 25: 441–447.

    Article  CAS  PubMed  Google Scholar 

  108. Ricca I, Compagno M, Ladetto M, Rocci A, Dell'Aquila M, Omede P et al. Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF. Leukemia 2005; 19: 644–651.

    Article  CAS  PubMed  Google Scholar 

  109. Bhatia R, Van HK, Palmer A, Komiya A, Slovak ML, Chang KL et al. Longitudinal assessment of hematopoietic abnormalities after autologous hematopoietic cell transplantation for lymphoma. J Clin Oncol 2005; 23: 6699–6711.

    Article  PubMed  Google Scholar 

  110. Vulliamy TJ, Knight SW, Mason PJ, Dokal I . Very short telomeres in the peripheral blood of patients with X-linked and autosomal dyskeratosis congenita. Blood Cells Mol Dis 2001; 27: 353–357.

    Article  CAS  PubMed  Google Scholar 

  111. Hoyeraal HM, Lamvik J, Moe PJ . Congenital hypoplastic thrombocytopenia and cerebral malformations in two brothers. Acta Paediatr Scand 1970; 59: 185–191.

    Article  CAS  PubMed  Google Scholar 

  112. Hreidarsson S, Kristjansson K, Johannesson G, Johannsson JH . A syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure. Acta Paediatr Scand 1988; 77: 773–775.

    Article  CAS  PubMed  Google Scholar 

  113. Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I . Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 2004; 36: 447–449.

    Article  CAS  PubMed  Google Scholar 

  114. Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998; 19: 32–38.

    Article  CAS  PubMed  Google Scholar 

  115. Mitchell JR, Wood E, Collins K . A telomerase component is defective in the human disease dyskeratosis congenita. Nature 1999; 402: 551–555.

    Article  CAS  PubMed  Google Scholar 

  116. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413: 432–435.

    Article  CAS  PubMed  Google Scholar 

  117. Vulliamy TJ, Marrone A, Knight SW, Walne A, Mason PJ, Dokal I . Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 2006; 107: 2680–2685.

    Article  CAS  PubMed  Google Scholar 

  118. Keith WN, Vulliamy T, Zhao J, Ar C, Erzik C, Bilsland A et al. A mutation in a functional Sp1 binding site of the telomerase RNA gene (hTERC) promoter in a patient with paroxysmal nocturnal haemoglobinuria. BMC Blood Disord 2004; 4: 3.

    PubMed  PubMed Central  Google Scholar 

  119. Karadimitris A, Araten DJ, Luzzatto L, Notaro R . Severe telomere shortening in patients with paroxysmal nocturnal hemoglobinuria affects both GPI− and GPI+ hematopoiesis. Blood 2003; 102: 514–516.

    Article  CAS  PubMed  Google Scholar 

  120. Beier F, Balabanov S, Buckley T, Dietz K, Hartmann U, Rojewski M et al. Accelerated telomere shortening in glycosylphosphatidylinositol (GPI)-negative compared with GPI-positive granulocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) detected by proaerolysin flow-FISH. Blood 2005; 106: 531–533.

    Article  CAS  PubMed  Google Scholar 

  121. Marsh JC, Chang J, Testa NG, Hows JM, Dexter TM . The hematopoietic defect in aplastic anemia assessed by long-term marrow culture. Blood 1990; 76: 1748–1757.

    CAS  PubMed  Google Scholar 

  122. Maciejewski JP, Anderson S, Katevas P, Young NS . Phenotypic and functional analysis of bone marrow progenitor cell compartment in bone marrow failure. Br J Haematol 1994; 87: 227–234.

    Article  CAS  PubMed  Google Scholar 

  123. Scopes J, Bagnara M, Gordon-Smith EC, Ball SE, Gibson FM . Haemopoietic progenitor cells are reduced in aplastic anaemia. Br J Haematol 1994; 86: 427–430.

    Article  CAS  PubMed  Google Scholar 

  124. Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS . A severe and consistent deficit in marrow and circulating primitive hematopoietic cells (long-term culture-initiating cells) in acquired aplastic anemia. Blood 1996; 88: 1983–1991.

    CAS  PubMed  Google Scholar 

  125. Schrezenmeier H, Jenal M, Herrmann F, Heimpel H, Raghavachar A . Quantitative analysis of cobblestone area-forming cells in bone marrow of patients with aplastic anemia by limiting dilution assay. Blood 1996; 88: 4474–4480.

    CAS  PubMed  Google Scholar 

  126. Podesta M, Piaggio G, Frassoni F, Pitto A, Zikos P, Sessarego M et al. The assessment of the hematopoietic reservoir after immunosuppressive therapy or bone marrow transplantation in severe aplastic anemia. Blood 1998; 91: 1959–1965.

    CAS  PubMed  Google Scholar 

  127. Bacigalupo A, Figari O, Tong J, Piaggio G, Miceli S, Frassoni F et al. Long-term marrow culture in patients with aplastic anemia compared with marrow transplant recipients and normal controls. Exp Hematol 1992; 20: 425–430.

    CAS  PubMed  Google Scholar 

  128. Tichelli A, Gratwohl A, Nissen C, Speck B . Late clonal complications in severe aplastic anemia. Leukemia Lymphoma 1994; 12: 167–175.

    Article  CAS  PubMed  Google Scholar 

  129. Brummendorf TH, Maciejewski JP, Mak J, Young NS, Lansdorp PM . Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood 2001; 97: 895–900.

    Article  CAS  PubMed  Google Scholar 

  130. Brummendorf TH, Rufer N, Holyoake TL, Maciejewski J, Barnett MJ, Eaves CJ et al. Telomere length dynamics in normal individuals and in patients with hematopoietic stem cell-associated disorders. Ann NY Acad Sci 2001; 938: 293–303.

    Article  CAS  PubMed  Google Scholar 

  131. Yamaguchi H, Baerlocher GM, Lansdorp PM, Chanock SJ, Nunez O, Sloand E et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood 2003; 102: 916–918.

    Article  CAS  PubMed  Google Scholar 

  132. Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 2003; 362: 1628–1630.

    Article  CAS  PubMed  Google Scholar 

  133. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 2005; 352: 1413–1424.

    Article  CAS  PubMed  Google Scholar 

  134. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV . Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333: 1253–1258.

    Article  CAS  PubMed  Google Scholar 

  135. Karadimitris A, Luzzatto L . The cellular pathogenesis of paroxysmal nocturnal haemoglobinuria. Leukemia 2001; 15: 1148–1152.

    Article  CAS  PubMed  Google Scholar 

  136. Dunn DE, Ware RE, Parker CJ, Mishoe HO, Young NS . Research directions in paroxysmal nocturnal hemoglobinuria. Immunol Today 1999; 20: 168–171.

    Article  CAS  PubMed  Google Scholar 

  137. Karadimitris A, Manavalan JS, Thaler HT, Notaro R, Araten DJ, Nafa K et al. Abnormal T-cell repertoire is consistent with immune process underlying the pathogenesis of paroxysmal nocturnal hemoglobinuria. Blood 2000; 96: 2613–2620.

    CAS  PubMed  Google Scholar 

  138. Brummendorf TH, Holyoake TL, Rufer N, Barnett MJ, Schulzer M, Eaves CJ et al. Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood 2000; 95: 1883–1890.

    CAS  PubMed  Google Scholar 

  139. Brummendorf TH, Ersoz I, Hartmann U, Balabanov S, Wolke H, Paschka P et al. Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia. Ann NY Acad Sci 2003; 996: 26–38.

    Article  PubMed  Google Scholar 

  140. Brummendorf TH, Ersoez I, Hartmann U, Bartolovic K, Balabanov S, Wahl A et al. Telomere length in peripheral blood cells reflects response to treatment with Imatinib in patients with chronic myeloid leukemia. Blood 2003; 101: 375–376.

    Article  CAS  PubMed  Google Scholar 

  141. Hartmann U, Balabanov S, Ziegler P, Fellenberg J, van der KH, Duyster J et al. Telomere length and telomerase activity in the BCR-ABL-transformed murine Pro-B cell line BaF3 is unaffected by treatment with imatinib. Exp Hematol 2005; 33: 542–549.

    Article  CAS  PubMed  Google Scholar 

  142. Drummond M, Lennard A, Brummendorf T, Holyoake T . Telomere shortening correlates with prognostic score at diagnosis and proceeds rapidly during progression of chronic myeloid leukemia. Leukemia Lymphoma 2004; 45: 1775–1781.

    Article  CAS  PubMed  Google Scholar 

  143. Drummond MW, Hoare SF, Monaghan A, Graham SM, Alcorn MJ, Keith WN et al. Dysregulated expression of the major telomerase components in leukaemic stem cells. Leukemia 2005; 19: 381–389.

    Article  CAS  PubMed  Google Scholar 

  144. Fialkow PJ, Gartler SM, Yoshida A . Clonal origin of chronic myelocytic leukemia in man. Proc Natl Acad Sci USA 1967; 58: 1468–1471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Raskind WH, Fialkow PJ . The use of cell markers in the study of human hematopoietic neoplasia. Adv Cancer Res 1987, 49127–49167.

  146. Fialkow PJ, Faguet GB, Jacobson RJ, Vaidya K, Murphy S . Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood 1981; 58: 916–919.

    CAS  PubMed  Google Scholar 

  147. Raskind WH, Ferraris AM, Najfeld V, Jacobson RJ, Moohr JW, Fialkow PJ . Further evidence for the existence of a clonal Ph-negative stage in some cases of Ph-positive chronic myelocytic leukemia. Leukemia 1993; 7: 1163–1167.

    CAS  PubMed  Google Scholar 

  148. Gilliland DG, Blanchard KL, Levy J, Perrin S, Bunn HF . Clonality in myeloproliferative disorders: analysis by means of the polymerase chain reaction. Proc Natl Acad Sci USA 1991; 88: 6848–6852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ferraris AM, Mangerini R, Racchi O, Rapezzi D, Rolfo M, Casciaro S et al. Heterogeneity of clonal development in chronic myeloproliferative disorders. Am J Hematol 1999; 60: 158–160.

    Article  CAS  PubMed  Google Scholar 

  150. Gilliland DG, Blanchard KL, Bunn HF . Clonality in acquired hematologic disorders. Annu Rev Med 1991; 42: 491–506.

    Article  CAS  PubMed  Google Scholar 

  151. Ferraris AM, Pujic N, Mangerini R, Rapezzi D, Gallamini A, Racchi O et al. Clonal granulocytes in polycythaemia vera and essential thrombocythaemia have shortened telomeres. Br J Haematol 2005; 130: 391–393.

    Article  CAS  PubMed  Google Scholar 

  152. Terasaki Y, Okumura H, Ohtake S, Nakao S . Accelerated telomere length shortening in granulocytes: a diagnostic marker for myeloproliferative diseases. Exp Hematol 2002; 30: 1399–1404.

    Article  CAS  PubMed  Google Scholar 

  153. Ferraris AM, Mangerini R, Pujic N, Racchi O, Rapezzi D, Gallamini A et al. High telomerase activity in granulocytes from clonal polycythemia vera and essential thrombocythemia. Blood 2005; 105: 2138–2140.

    Article  CAS  PubMed  Google Scholar 

  154. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.

    Article  CAS  PubMed  Google Scholar 

  155. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.

    Article  CAS  PubMed  Google Scholar 

  156. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397.

    Article  CAS  PubMed  Google Scholar 

  157. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005; 106: 2162–2168.

    Article  CAS  PubMed  Google Scholar 

  158. Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005; 366: 1945–1953.

    Article  CAS  PubMed  Google Scholar 

  159. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  160. Boultwood J, Fidler C, Kusec R, Rack K, Elliott PJ, Atoyebi O et al. Telomere length in myelodysplastic syndromes. Am J Hematol 1997; 56: 266–271.

    Article  CAS  PubMed  Google Scholar 

  161. Engelhardt M, Mackenzie K, Drullinsky P, Silver RT, Moore MA . Telomerase activity and telomere length in acute and chronic leukemia, pre- and post-ex vivo culture. Cancer Res 2000; 60: 610–617.

    CAS  PubMed  Google Scholar 

  162. Li B, Yang J, Andrews C, Chen YX, Toofanfard P, Huang RW et al. Telomerase activity in preleukemia and acute myelogenous leukemia. Leukemia Lymphoma 2000; 36: 579–587.

    Article  PubMed  Google Scholar 

  163. Li Y, Wu J, Wang L, Chen F, Hu L . Detection of telomerase activity and the expression of telomerase subunits in the patients with acute myelogenous leukaemia. J Huazhong Univ Sci Technol Med Sci 2004; 24: 48–51.

    Article  CAS  Google Scholar 

  164. Ohyashiki JH, Ohyashiki K, Iwama H, Hayashi S, Toyama K, Shay JW . Clinical implications of telomerase activity levels in acute leukemia. Clin Cancer Res 1997; 3: 619–625.

    CAS  PubMed  Google Scholar 

  165. Ohyashiki K, Iwama H, Yahata N, Tauchi T, Kawakubo K, Shimamoto T et al. Telomere dynamics in myelodysplastic syndromes and acute leukemic transformation. Leukemia Lymphoma 2001; 42: 291–299.

    Article  CAS  PubMed  Google Scholar 

  166. Sieglova Z, Zilovcova S, Cermak J, Rihova H, Brezinova D, Dvorakova R et al. Dynamics of telomere erosion and its association with genome instability in myelodysplastic syndromes (MDS) and acute myelogenous leukemia arising from MDS: a marker of disease prognosis? Leukemia Res 2004; 28: 1013–1021.

    Article  CAS  Google Scholar 

  167. Verstovsek S, Manshouri T, Smith FO, Giles FJ, Cortes J, Estey E et al. Telomerase activity is prognostic in pediatric patients with acute myeloid leukemia: comparison with adult acute myeloid leukemia. Cancer 2003; 97: 2212–2217.

    Article  CAS  PubMed  Google Scholar 

  168. Hartmann U, Brummendorf TH, Balabanov S, Thiede C, Illme T, Schaich M . Telomere length and hTERT expression in patients with acute myeloid leukemia correlates with chromosomal abnormalities. Haematologica 2005; 90: 307–316.

    CAS  PubMed  Google Scholar 

  169. Hao LY, Armanios M, Strong MA, Karim B, Feldser DM, Huso D et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 2005; 123: 1121–1131.

    Article  CAS  PubMed  Google Scholar 

  170. Hemann MT, Strong MA, Hao LY, Greider CW . The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 2001; 107: 67–77.

    Article  CAS  PubMed  Google Scholar 

  171. Swiggers SJ, Kuijpers MA, de Cort MJ, Beverloo HB, Zijlmans JM . Critically short telomeres in acute myeloid leukemia with loss or gain of parts of chromosomes. Genes Chromosomes Cancer 2006; 45: 247–256.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Tessa Holyoake, Glasgow and Carsten Bokemeyer, Hamburg, for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Department of Oncology and Hematology with Sections Bone Marrow Transplantation and Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    T H Brümmendorf & S Balabanov

Authors
  1. T H Brümmendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Balabanov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T H Brümmendorf.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brümmendorf, T., Balabanov, S. Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover. Leukemia 20, 1706–1716 (2006). https://doi.org/10.1038/sj.leu.2404339

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404339

Keywords

This article is cited by

Search

Advanced search

Quick links