Short Dysfunctional Telomere is Highly Predictive of Dismal Outcome in MDS but Not in AML Patients
Abstract
Background: A trigger for initiation the clonal hematopoietic stem cells disorders could be short telomere length, probably due to chromosomal instability. The relationship between relative telomere length (RTL) and the two linked hematological stem cell disorders, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), is still unclear.
Material and Methods: We evaluated the role of RTL in MDS (n=96) and AML (n=130) at the time of diagnosis using a real time quantitative polymerase chain reaction (RT-PCR) technique. The median value of RTL (1) was set as the cutoff for statistical comparison. Overall survival (OS) is defined as the time from diagnosis to death or last follow-up.
Results: RTL was significantly longer in both MDS and AML cases versus control (p<0.0001) and was significantly longer in MDS versus AML cases (p =0.03). RTL correlated negatively with age in MDS (p <0.0001) but not in AML cases. RTL was also significantly shorter in MDS cases with pancytopenia and poor risk cytogenetics (p < 0.0001 for each) and short RTL was significantly associated with inferior survival (p = 0.007), while RTL showed no significant impact on OS in AML cases. Moreover, short RTL retained independent prognostic value in multivariate analysis (HR= 3.42 [95% CI, 8.97-19.35], p = 0.004).
Conclusion: RTL showed an association with both AML and MDS; however, short RTL was an independent poor prognostic factor in MDS patients only.
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3. Greenberg PL. Molecular and genetic features of myelodysplastic syndromes. Int J Lab Hematol. 2012;34(3):215-22.
4. Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241-7.
5. McKerrell T, Park N, Moreno T, Grove CS, et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015;10(8):1239-45.
6. Deville L, Hillion J, Segal-Bendirdjian E. Telomerase regulation in hematological cancers: a matter of stemness? Biochim Biophys Acta. 2009;1792(4):229-39.
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8. Rode L, Nordestgaard BG, Bojesen SE. Peripheral blood leukocyte telomere length and mortality among 64,637 individuals from the general population. J Natl Cancer Inst. 2015;107(6):djv074.
9. Pepper C, Baird DM. Shortened telomeres: a driving force behind leukemia? Future Oncol. 2010;6(11):1681-6.
10. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
11. Campisi J. Cellular Senescence, Aging and Cancer. ScientificWorldJournal. 2001;1:65.
12. Williams J, Heppel NH, Britt-Compton B, et al. Telomere length is an independent prognostic marker in MDS but not in de novo AML. Br J Haematol. 2017;178(2):240-9.
13. Gadji M, Adebayo Awe J, Rodrigues P, et al. Profiling three-dimensional nuclear telomeric architecture of myelodysplastic syndromes and acute myeloid leukemia defines patient subgroups. Clin Cancer Res. 2012;18(12):3293-304.
14. Colla S, Ong DS, Ogoti Y, et al. Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell. 2015;27(5):644-57.
15. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002;30(10):e47.
16. Nomenclature SCoHC, Mitelman F. ISCN 1995 : an international system for human cytogenetic nomenclature (1995) : recommendations of the International Standing Committee on Human Cytogenetic Nomenclature, Memphis, Tennessee, USA, October 9-13, 1994: New York : Karger; 1995.
17. Lansdorp PM. Maintenance of telomere length in AML. Blood Adv. 2017;1(25):2467-72.
18. Lin TT, Norris K, Heppel NH, et al. Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. Br J Haematol. 2014;167(2):214-23.
19. Wysoczanska B, Dratwa M, Gebura K, et al. Variability within the human TERT gene, telomere length and predisposition to chronic lymphocytic leukemia. Onco Targets Ther. 2019;12:4309-20.
20. Simpson K, Jones RE, Grimstead JW, et al. Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients. Mol Oncol. 2015;9(6):1186-93.
21. Schratz KE, Haley L, Danoff SK, et al. Cancer spectrum and outcomes in the Mendelian short telomere syndromes. Blood. 2020; 135(22): 1945-1956.
22. Martens UM, Brass V, Sedlacek L, et al. Telomere maintenance in human B lymphocytes. Br J Haematol. 2002;119(3):810-8.
23. Gorenjak V, Akbar S, Stathopoulou MG, et al. The future of telomere length in personalized medicine. Front Biosci (Landmark Ed). 2018;23:1628-54.
24. Hosnijeh FS, Matullo G, Russo A, et al. Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study. Int J Cancer. 2014;135(12):2910-7.
25. Xie H, Wu X, Wang S, et al. Long telomeres in peripheral blood leukocytes are associated with an increased risk of soft tissue sarcoma. Cancer. 2013;119(10):1885-91.
26. Dagg RA, Pickett HA, Neumann AA, et al. Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres. Cell Rep. 2017;19(12):2544-56.
27. Hackett JA, Greider CW. Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene. 2002;21(4):619-26.
28. Rode L, Nordestgaard BG, Bojesen SE. Long telomeres and cancer risk among 95 568 individuals from the general population. Int J Epidemiol. 2016;45(5):1634-43.
29. Kröger N, Zabelina T, de Wreede L, et al. Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia. 2013;27(3):604-9.
30. Rollison DE, Epling-Burnette PK, Park JY, et al. Telomere length in myelodysplastic syndromes. Leuk Lymphoma. 2011;52(8):1528-36.
31. Kirwan M, Beswick R, Vulliamy T, et al. Exogenous TERC alone can enhance proliferative potential, telomerase activity and telomere length in lymphocytes from dyskeratosis congenita patients. Br J Haematol. 2009;144(5):771-81.
32. Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2013;6(3):327-37.
33. Gohring G, Lange K, Hofmann W, et al. Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide. Leukemia. 2012;26(2):356-8.
34. Ohyashiki JH, Iwama H, Yahata N, et al. Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes. Clin Cancer Res. 1999;5(5):1155-60.
35. Capper R, Britt-Compton B, Tankimanova M, et al. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev. 2007;21(19):2495-508.
36. Hwang SM, Kim SY, Kim JA, et al. Short telomere length and its correlation with gene mutations in myelodysplastic syndrome. J Hematol Oncol. 2016;9(1):62.
37. Kishtagari A, Watts J. Biological and clinical implications of telomere dysfunction in myeloid malignancies. Ther Adv Hematol. 2017;8(11):317-26.
38. Gessner A, Thomas M, Castro PG, et al. Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT. Leukemia. 2010;24(10):1751-9.
39. Capraro V, Zane L, Poncet D, et al. Telomere deregulations possess cytogenetic, phenotype, and prognostic specificities in acute leukemias. Exp Hematol. 2011;39(2):195-202 e2.
40. Watts JM, Dumitriu B, Hilden P, et al. Telomere length and associations with somatic mutations and clinical outcomes in acute myeloid leukemia. Leuk Res. 2016;49:62-5.
41. Wang L, Xiao H, Zhang X, et al. The role of telomeres and telomerase in hematologic malignancies and hematopoietic stem cell transplantation. J Hematol Oncol. 2014;7:61.
42. Warny M, Helby J, Sengelov H, et al. Bone marrow mononuclear cell telomere length in acute myeloid leukaemia and high-risk myelodysplastic syndrome. Eur J Haematol. 2019;102(3):218-26.
2. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-51.
3. Greenberg PL. Molecular and genetic features of myelodysplastic syndromes. Int J Lab Hematol. 2012;34(3):215-22.
4. Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241-7.
5. McKerrell T, Park N, Moreno T, Grove CS, et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015;10(8):1239-45.
6. Deville L, Hillion J, Segal-Bendirdjian E. Telomerase regulation in hematological cancers: a matter of stemness? Biochim Biophys Acta. 2009;1792(4):229-39.
7. Aubert G, Lansdorp PM. Telomeres and aging. Physiol Rev. 2008;88(2):557-79.
8. Rode L, Nordestgaard BG, Bojesen SE. Peripheral blood leukocyte telomere length and mortality among 64,637 individuals from the general population. J Natl Cancer Inst. 2015;107(6):djv074.
9. Pepper C, Baird DM. Shortened telomeres: a driving force behind leukemia? Future Oncol. 2010;6(11):1681-6.
10. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
11. Campisi J. Cellular Senescence, Aging and Cancer. ScientificWorldJournal. 2001;1:65.
12. Williams J, Heppel NH, Britt-Compton B, et al. Telomere length is an independent prognostic marker in MDS but not in de novo AML. Br J Haematol. 2017;178(2):240-9.
13. Gadji M, Adebayo Awe J, Rodrigues P, et al. Profiling three-dimensional nuclear telomeric architecture of myelodysplastic syndromes and acute myeloid leukemia defines patient subgroups. Clin Cancer Res. 2012;18(12):3293-304.
14. Colla S, Ong DS, Ogoti Y, et al. Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell. 2015;27(5):644-57.
15. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002;30(10):e47.
16. Nomenclature SCoHC, Mitelman F. ISCN 1995 : an international system for human cytogenetic nomenclature (1995) : recommendations of the International Standing Committee on Human Cytogenetic Nomenclature, Memphis, Tennessee, USA, October 9-13, 1994: New York : Karger; 1995.
17. Lansdorp PM. Maintenance of telomere length in AML. Blood Adv. 2017;1(25):2467-72.
18. Lin TT, Norris K, Heppel NH, et al. Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. Br J Haematol. 2014;167(2):214-23.
19. Wysoczanska B, Dratwa M, Gebura K, et al. Variability within the human TERT gene, telomere length and predisposition to chronic lymphocytic leukemia. Onco Targets Ther. 2019;12:4309-20.
20. Simpson K, Jones RE, Grimstead JW, et al. Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients. Mol Oncol. 2015;9(6):1186-93.
21. Schratz KE, Haley L, Danoff SK, et al. Cancer spectrum and outcomes in the Mendelian short telomere syndromes. Blood. 2020; 135(22): 1945-1956.
22. Martens UM, Brass V, Sedlacek L, et al. Telomere maintenance in human B lymphocytes. Br J Haematol. 2002;119(3):810-8.
23. Gorenjak V, Akbar S, Stathopoulou MG, et al. The future of telomere length in personalized medicine. Front Biosci (Landmark Ed). 2018;23:1628-54.
24. Hosnijeh FS, Matullo G, Russo A, et al. Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study. Int J Cancer. 2014;135(12):2910-7.
25. Xie H, Wu X, Wang S, et al. Long telomeres in peripheral blood leukocytes are associated with an increased risk of soft tissue sarcoma. Cancer. 2013;119(10):1885-91.
26. Dagg RA, Pickett HA, Neumann AA, et al. Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres. Cell Rep. 2017;19(12):2544-56.
27. Hackett JA, Greider CW. Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene. 2002;21(4):619-26.
28. Rode L, Nordestgaard BG, Bojesen SE. Long telomeres and cancer risk among 95 568 individuals from the general population. Int J Epidemiol. 2016;45(5):1634-43.
29. Kröger N, Zabelina T, de Wreede L, et al. Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia. 2013;27(3):604-9.
30. Rollison DE, Epling-Burnette PK, Park JY, et al. Telomere length in myelodysplastic syndromes. Leuk Lymphoma. 2011;52(8):1528-36.
31. Kirwan M, Beswick R, Vulliamy T, et al. Exogenous TERC alone can enhance proliferative potential, telomerase activity and telomere length in lymphocytes from dyskeratosis congenita patients. Br J Haematol. 2009;144(5):771-81.
32. Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2013;6(3):327-37.
33. Gohring G, Lange K, Hofmann W, et al. Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide. Leukemia. 2012;26(2):356-8.
34. Ohyashiki JH, Iwama H, Yahata N, et al. Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes. Clin Cancer Res. 1999;5(5):1155-60.
35. Capper R, Britt-Compton B, Tankimanova M, et al. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev. 2007;21(19):2495-508.
36. Hwang SM, Kim SY, Kim JA, et al. Short telomere length and its correlation with gene mutations in myelodysplastic syndrome. J Hematol Oncol. 2016;9(1):62.
37. Kishtagari A, Watts J. Biological and clinical implications of telomere dysfunction in myeloid malignancies. Ther Adv Hematol. 2017;8(11):317-26.
38. Gessner A, Thomas M, Castro PG, et al. Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT. Leukemia. 2010;24(10):1751-9.
39. Capraro V, Zane L, Poncet D, et al. Telomere deregulations possess cytogenetic, phenotype, and prognostic specificities in acute leukemias. Exp Hematol. 2011;39(2):195-202 e2.
40. Watts JM, Dumitriu B, Hilden P, et al. Telomere length and associations with somatic mutations and clinical outcomes in acute myeloid leukemia. Leuk Res. 2016;49:62-5.
41. Wang L, Xiao H, Zhang X, et al. The role of telomeres and telomerase in hematologic malignancies and hematopoietic stem cell transplantation. J Hematol Oncol. 2014;7:61.
42. Warny M, Helby J, Sengelov H, et al. Bone marrow mononuclear cell telomere length in acute myeloid leukaemia and high-risk myelodysplastic syndrome. Eur J Haematol. 2019;102(3):218-26.
| Files | ||
| Issue | Vol 14, No 3 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v14i3.3728 | |
| Keywords | ||
| Relative telomere length; Myelodysplatic syndromes; Acute myeloid leukemia | ||
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How to Cite
1.
Menshawy N, Ashwah S, Ebrahim M. Short Dysfunctional Telomere is Highly Predictive of Dismal Outcome in MDS but Not in AML Patients. Int J Hematol Oncol Stem Cell Res. 2020;14(3):188-199.
