Abstract
In cell and animal models, telomere erosion promotes chromosomal instability via breakage-fusion-bridge cycles, contributing to the early stages of tumorigenesis. However, evidence involving short telomeres in cancer development in humans is scarce, epidemiological and indirect. Here we directly implicate telomere shortening as a critical molecular event for malignant evolution in aplastic anemia (AA). Patients’ telomere lengths at diagnosis of AA, while comparable to age-matched controls, inversely correlated with the probability of developing a cytogenetically abnormal clone. A significantly increased number of telomere signal-free chromosomal ends and chromosomal numerical and structural abnormalities were observed in bone marrow cells of patients with shorter telomeres in comparison with patients with longer telomeres and healthy subjects. The proportion of monosomy-7 cells in the bone marrow at diagnosis of AA inversely correlated with telomere length, years before the emergence of an autonomous and clinically detectable abnormal clone. Marrow cells of clinically healthy individuals carrying loss-of-function telomerase mutations and with extremely short telomeres also showed chromosomal instability in vitro. These results provide the first clinical direct evidence in humans that short telomeres in hematopoietic cells are dysfunctional, mediate chromosomal instability and predispose to malignant transformation in a human disease.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Young NS, Calado RT, Scheinberg P . Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 2006; 108: 2511–2521.
Yamaguchi H, Calado RT, Ly H, Baerlocher GM, Kajigaya S, Chanock SJ et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Eng J Med 2005; 352: 1413–1424.
Calado RT, Young NS . Telomere diseases. N Engl J Med 2009; 361: 2353–2365.
Walne AJ, Dokal I . Advances in the understanding of dyskeratosis congenita. Br J Haematol 2009; 145: 164–172.
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.
Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason P et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413: 432–435.
Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP . TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 2008; 82: 501–509.
Socie G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A . Late clonal diseases of treated aplastic anemia. Semin Hematol 2000; 37: 91–101.
Rosenfeld S, Follman D, Nuñez O, Young NS . Antithymocyte globulin and cyclosporine for severe aplastic anemia. Association between hematologic response and long-term outcome. JAMA 2003; 289: 1130–1135.
Alter BP, Giri N, Savage SA, Rosenberg PS . Cancer in dyskeratosis congenita. Blood 2009; 113: 6549–6557.
Calado RT, Regal JA, Hills M, Yewdell WT, Dalmazzo LF, Zago MA et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc Nat Acad Sci USA 2009; 106: 1187–1192.
Kirwan M, Vulliamy T, Marrone A, Walne AJ, Beswick R, Hillmen P et al. Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum Mutat 2009; 30: 1567–1573.
McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G et al. Lung cancer susceptibility locus at 5p15.33. Nat Genet 2008; 40: 1404–1406.
Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat Genet 2009; 41: 221–227.
Willeit P, Willeit J, Mayr A, Weger S, Oberhollenzer F, Brandstatter A et al. Telomere length and risk of incident cancer and cancer mortality. JAMA 2010; 304: 69–75.
Artandi SE, Chang S, Lee S-L, Alson S, Gottlieb GJ, Chin L et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 2000; 406: 641–645.
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.
Begus-Nahrmann Y, Lechel A, Obenauf AC, Nalapareddy K, Peit E, Hoffmann E et al. p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice. Nat Genet 2009; 41: 1138–1143.
Scheinberg P, Wu CO, Nunez O, Young NS . Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol 2009; 144: 206–216.
Calado RT, Brudno J, Mehta P, Kovacs JJ, Wu C, Zago MA et al. Constitutional telomerase mutations are genetic risk factors for the development of cirrhosis. Hepatology 2011; 53: 1600–1607.
Scheinberg P, Cooper JN, Sloand EM, Wu CO, Calado RT, Young NS . Association of telomere length of peripheral blood leukocytes predicts hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA 2010; 304: 1358–1364.
Schrock E, du MS, Veldman T, Schoell B, Wienberg J, Ferguson-Smith MA et al. Multicolor spectral karyotyping of human chromosomes. Science 1996; 273: 494–497.
Maciejewski JP, Risitano AM, Sloand EM, Nunez O, Young NS . Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 2002; 99: 3129–3135.
Tiu R, Gondek L, O’Keefe C, Maciejewski J . Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes. Leukemia 2007, 1648–1657.
Mikhailova N, Sessarego M, Fugazza G, Caimo A, De Filippi S, van Lint MT et al. Cytogenetic abnormalities in patients with severe aplastic anemia. Haematologica 1996; 81: 418–422.
Muntoni A, Reddel RR . The first molecular details of ALT in human tumor cells. Hum Mol Genet 2005; 14: R191–R196.
Sloand EM, Yong AS, Ramkissoon S, Solomou EE, Bruno TC, Kim S et al. Granulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells bearing the isoform IV receptor. Proc Natl Acad Sci USA 2007; 103: 14483–14488.
Hackett JA, Feldser DM, Greider CW . Telomere dysfunction increases mutation rate and genomic instability. Cell 2001; 106: 275–286.
Wong KK, Chang S, Weiler SR, Ganesan S, Chaudhuri J, Zhu C et al. Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat Genet 2000; 26: 85–88.
Hemann MT, Greider CW . Wild-derived inbred mouse strains have short telomeres. Nucleic Acids Res 2000; 28: 4474–4478.
Chiang J, Calado R, Hathcock K, Lansdorp PM, Young NS, Hodes R . Telomere length is inherited with resetting of the telomere set-poing. Proc Natl Acad Sci USA 2010; 107: 01148–10153.
Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA . Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 2000; 287: 1253–1258.
Liu T, Chung MJ, Ullenbruch M, Yu H, Jin H, Hu B et al. Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice. J Clin Invest 2007; 117: 3800–3809.
Hockemeyer D, Palm W, Wang RC, Couto SS, de LT . Engineered telomere degradation models dyskeratosis congenita. Genes Dev 2008; 22: 1773–1785.
Blasco MA . Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 2005; 6: 611–622.
Pampalona J, Soler D, Genesca A, Tusell L . Whole chromosome loss is promoted by telomere dysfunction in primary cells. Genes Chromosomes Cancer 2010; 49: 368–378.
Davoli T, Denchi EL, de LT . Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 2010; 141: 81–93.
Risques RA, Baughan TL, li X, Odze RD, Blount PL, Ayub K et al. Leukocyte telomere length predicts cancer risk in Barrett's esophagus. Cancer Epidemiol Biomarkers Prev 2007; 16: 2649–2655.
O’Sullivan JN, Bronner MP, Brentnall TA, Finley JC, Shen WT, Emerson S et al. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 2002; 32: 280–284.
Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 2007; 5: e110.
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.
Acknowledgements
This work was entirely supported by the NIH Intramural Research Program. Dr Cooper's research year was made possible through the Clinical Research Training Program (CRTP), a public–private partnership supported jointly by the NIH and Pfizer (grant to the Foundation for NIH from Pfizer). EMS is deceased. We are grateful to Olga Nunez, RN and Barbara Weinstein, RN for patient care and sample collection.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Calado, R., Cooper, J., Padilla-Nash, H. et al. Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia. Leukemia 26, 700–707 (2012). https://doi.org/10.1038/leu.2011.272
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2011.272
Keywords
This article is cited by
-
Studying the pathogenicity of 26 variants characterized in the first molecular analyses of Egyptian aplastic anemia patients
Journal of Genetic Engineering and Biotechnology (2023)
-
Severe telomere shortening in Fanconi anemia complementation group L
Molecular Biology Reports (2021)
-
Long-term outcomes of 172 children with severe aplastic anemia treated with rabbit antithymocyte globulin and cyclosporine
Annals of Hematology (2021)
-
Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells
Stem Cell Reviews and Reports (2020)
-
Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes
Orphanet Journal of Rare Diseases (2019)