Skip to main content

Advertisement

SpringerLink
Log in

Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders

  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Telomere biology disorders (TBDs) are germline-inherited conditions characterized by reduction in telomerase function, accelerated shortening of telomeres, predisposition to organ-failure syndromes, and increased risk of neoplasms, especially myeloid malignancies. In normal cells, critically short telomeres trigger apoptosis and/or cellular senescence. However, the evolutionary mechanism by which TBD-related telomerase-deficient cells can overcome this fitness constraint remains elusive.

Recent Findings

Preliminary data suggests the existence of adaptive somatic mosaic states characterized by variants in TBD-related genes and maladaptive somatic mosaic states that attempt to overcome hematopoietic fitness constraints by alternative methods leading to clonal hematopoiesis.

Summary

TBDs are both rare and highly heterogeneous in presentation, and the association of TBD with malignant transformation is unclear. Understanding the clonal complexity and mechanisms behind TBD-associated molecular signatures that lead to somatic adaptation in the setting of defective hematopoiesis will help inform therapy and treatment for this set of diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. McNally EJ, Luncsford PJ, Armanios M. Long telomeres and cancer risk: the price of cellular immortality. J Clin Invest. 2019;129(9):3474–81.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Blackburn EH, Gall JG. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J Mol Biol. 1978;120(1):33–53.

    Article  PubMed  CAS  Google Scholar 

  3. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in tetrahymena extracts. Cell. 1985;43(2, Part 1):405–13.

    Article  PubMed  CAS  Google Scholar 

  4. Blackburn EH, Greider CW, Szostak JW. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med. 2006;12(10):1133–8.

    Article  PubMed  CAS  Google Scholar 

  5. O’Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. 2010;11(3):171–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Harley CB. Telomere loss: mitotic clock or genetic time bomb? Mutat Res/DNAging. 1991;256(2):271–82.

    Article  CAS  Google Scholar 

  7. Greider CW. Telomerase is processive. Mol Cell Biol. 1991;11(9):4572–80.

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Cesare AJ, Reddel RR. Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet. 2010;11(5):319–30.

    Article  PubMed  CAS  Google Scholar 

  9. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25(3):585–621.

    Article  PubMed  CAS  Google Scholar 

  10. van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509(7501):439–46.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Blackburn EH, Epel ES, Lin J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science. 2015;350(6265):1193–8.

    Article  PubMed  CAS  Google Scholar 

  12. Dunham MA, Neumann AA, Fasching CL, Reddel RR. Telomere maintenance by recombination in human cells. Nat Genet. 2000;26(4):447–50.

    Article  PubMed  CAS  Google Scholar 

  13. Gravekamp C, Chandra D. Aging and cancer vaccines. Crit Rev Oncog. 2013;18(6):585–95.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 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(2):353–7.

    Article  PubMed  CAS  Google Scholar 

  15. Bertuch AA. The molecular genetics of the telomere biology disorders. RNA Biol. 2016;13(8):696–706.

    Article  PubMed  Google Scholar 

  16. Savage SA, Bertuch AA. The genetics and clinical manifestations of telomere biology disorders. Genet Med. 2010;12(12):753–64.

    Article  PubMed  Google Scholar 

  17. Shay JW, Wright WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet. 2019;20(5):299–309.

    Article  PubMed  CAS  Google Scholar 

  18. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317–26.

    Article  PubMed  CAS  Google Scholar 

  19. Feurstein S, Adegunsoye A, Mojsilovic D, Vij R, West DePersia AH, Rajagopal PS, et al. Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations. Blood Adv. 2020;4(19):4873–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Mangaonkar AA, Patnaik MM. Short telomere syndromes in clinical practice: bridging bench and bedside. Mayo Clin Proc. 2018;93(7):904–16.

    Article  PubMed  Google Scholar 

  21. Alter BP, Rosenberg PS, Giri N, Baerlocher GM, Lansdorp PM, Savage SA. Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica. 2012;97(3):353–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Blanche PA, Neelam G, Sharon AS, Philip SR. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018;103(1):30–9.

    Article  Google Scholar 

  23. Schratz KE, Haley L, Danoff SK, Blackford AL, DeZern AE, Gocke CD, et al. Cancer spectrum and outcomes in the Mendelian short telomere syndromes. Blood. 2020;135(22):1946–56. Description of the clinical outcomes of the TBD cohort assembled at Johns Hopkins. First report indicating that TBD patients present with increased CH and a different mutational signature compared to ARCH.

  24. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018;103(1):30–9. Description of the clinical outcomes of the TBD cohort assembled by the NIH describing higher risk to develop MN and specific characteristics of these patients.

  25. Schratz KE, Armanios M. Cancer and myeloid clonal evolution in the short telomere syndromes. Curr Opin Genet Dev. 2020;60:112–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019;366(6465):eaan4673.

  27. Fabre MA, de Almeida JG, Fiorillo E, Mitchell E, Damaskou A, Rak J, et al. The longitudinal dynamics and natural history of clonal haematopoiesis. Nature. 2022;606(7913):335–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Mitchell E, Spencer Chapman M, Williams N, Dawson KJ, Mende N, Calderbank EF, et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature. 2022;606(7913):343–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kusne Y, Xie Z, Patnaik MM. Clonal hematopoiesis: molecular and clinical implications. Leuk Res. 2022;113:106787.

    Article  PubMed  CAS  Google Scholar 

  30. Gregory JJ Jr, Wagner JE, Verlander PC, Levran O, Batish SD, Eide CR, et al. Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells. Proc Natl Acad Sci USA. 2001;98(5):2532–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Myers KC, Furutani E, Weller E, Siegele B, Galvin A, Arsenault V, et al. Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. Lancet Haematol. 2020;7(3):e238–46.

    Article  PubMed  Google Scholar 

  32. Gutierrez-Rodrigues F, Groarke EM, Clé DV, Patel BA, Donaires FS, Spitofsky N, et al. Clonal hematopoiesis in telomere biology disorders associates with the underlying germline defect and somatic mutations in POT1, PPM1D, and TERT promoter. Blood. 2021;138(Supplement 1):1111-. Description in more detail of the somatic mutational landscape observed in the larger number of TBD patients to date. Possible association between specific somatic events and germline mutations.

  33. Ferrer A, Mangaonkar AA, Patnaik MM. Clonal hematopoiesis and myeloid neoplasms in the context of telomere biology disorders. Curr Hematol Malig Rep. 2022;17(3):61–8.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pritzl SL, Gurney M, Badar T, Ferrer A, Lasho T, Finke C, et al. Clinical and molecular spectrum and prognostic outcomes of U2AF1 mutant clonal hematopoiesis- a prospective mayo clinic cohort study. Leuk Res. 2023;125:107007.

    Article  PubMed  CAS  Google Scholar 

  35. Schratz KE, Gaysinskaya V, Cosner ZL, DeBoy EA, Xiang Z, Kasch-Semenza L, et al. Somatic reversion impacts myelodysplastic syndromes and acute myeloid leukemia evolution in the short telomere disorders. J Clin Invest. 2021;131(18). Study of genetic rescue in the development of MDS/AML in TBD patients.

  36. Maryoung L, Yue Y, Young A, Newton CA, Barba C, van Oers NS, et al. Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations. J Clin Invest. 2017;127(3):982–6.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Revy P, Kannengiesser C, Bertuch AA. Genetics of human telomere biology disorders. Nat Rev Genet. 2023;24(2):86–108.

    Article  PubMed  CAS  Google Scholar 

  38. Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA. 1994;91(21):9857–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Armanios M, Alder JK, Parry EM, Karim B, Strong MA, Greider CW. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Human Genet. 2009;85(6):823–32.

    Article  CAS  Google Scholar 

  40. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194–8.

  41. Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13(17):1549–56.

    Article  PubMed  CAS  Google Scholar 

  42. Jacobs JJ, de Lange T. Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol. 2004;14(24):2302–8.

    Article  PubMed  CAS  Google Scholar 

  43. Sfeir A, de Lange T. Removal of shelterin reveals the telomere end-protection problem. Science. 2012;336(6081):593–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Lazzerini-Denchi E, Sfeir A. Stop pulling my strings — what telomeres taught us about the DNA damage response. Nat Rev Mol Cell Biol. 2016;17(6):364–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Kiss T, Fayet-Lebaron E, Jády BE. Box H/ACA small ribonucleoproteins. Mol Cell. 2010;37(5):597–606.

    Article  PubMed  Google Scholar 

  46. Darzacq X, Kittur N, Roy S, Shav-Tal Y, Singer RH, Meier UT. Stepwise RNP assembly at the site of H/ACA RNA transcription in human cells. J Cell Biol. 2006;173(2):207–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Schmidt JC, Cech TR. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev. 2015;29(11):1095–105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Roake CM, Artandi SE. Regulation of human telomerase in homeostasis and disease. Nat Rev Mol Cell Biol. 2020;21(7):384–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. 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(5349):349–52.

    Article  PubMed  CAS  Google Scholar 

  50. Chiba K, Lorbeer FK, Shain AH, McSwiggen DT, Schruf E, Oh A, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science. 2017;357(6358):1416–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Gutierrez-Rodrigues F, Donaires FS, Pinto A, Vicente A, Dillon LW, Clé DV, et al. Pathogenic TERT promoter variants in telomere diseases. Genet Med. 2019;21(7):1594–602.

    Article  PubMed  CAS  Google Scholar 

  52. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci. 2007;104(18):7552–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Du H-Y, Pumbo E, Manley P, Field JJ, Bayliss SJ, Wilson DB, et al. Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene. Blood. 2008;111(3):1128–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Aspesi A, Vallero S, Rocci A, Pavesi E, Lanciotti M, Ramenghi U, et al. Compound heterozygosity for two new TERT mutations in a patient with aplastic anemia. Pediatr Blood Cancer. 2010;55(3):550–3.

    Article  PubMed  Google Scholar 

  55. Gramatges MM, Qi X, Sasa GS, Chen JJL, Bertuch AA. A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome. Blood. 2013;121(18):3586–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Niaz A, Truong J, Manoleras A, Fox LC, Blombery P, Vasireddy RS, et al. Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder. Blood Adv. 2022;6(12):3779–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Çepni E, Satkın NB, Moheb LA, Rocha ME, Kayserili H. Biallelic TERT variant leads to Hoyeraal-Hreidarsson syndrome with additional dyskeratosis congenita findings. Am J Med Genet A. 2022;188(4):1226–32.

    Article  PubMed  Google Scholar 

  58. Stockklausner C, Raffel S, Klermund J, Bandapalli OR, Beier F, Brümmendorf TH, et al. A novel autosomal recessive TERT T1129P mutation in a dyskeratosis congenita family leads to cellular senescence and loss of CD34+ hematopoietic stem cells not reversible by mTOR-inhibition. Aging (Albany NY). 2015;7(11):911.

    Article  PubMed  CAS  Google Scholar 

  59. Marrone A, Walne A, Tamary H, Masunari Y, Kirwan M, Beswick R, et al. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood. 2007;110(13):4198–205.

    Article  PubMed  CAS  Google Scholar 

  60. 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(6854):432–5.

    Article  PubMed  CAS  Google Scholar 

  61. Nguyen THD, Tam J, Wu RA, Greber BJ, Toso D, Nogales E, et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature. 2018;557(7704):190–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. 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(1):32–8.

    Article  PubMed  CAS  Google Scholar 

  63. Knight SW, Heiss NS, Vulliamy TJ, Greschner S, Stavrides G, Pai GS, et al. X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am J Human Genet. 1999;65(1):50–8.

    Article  CAS  Google Scholar 

  64. Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, Masunari Y, et al. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet. 2007;16(13):1619–29.

    Article  PubMed  CAS  Google Scholar 

  65. Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M, Walne A, et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci. 2008;105(23):8073–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Benyelles M, O’Donohue M-F, Kermasson L, Lainey E, Borie R, Lagresle-Peyrou C, et al. NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal-Hreidarsson syndrome. Hum Mol Genet. 2020;29(6):907–22.

    Article  PubMed  CAS  Google Scholar 

  67. Zhong F, Savage SA, Shkreli M, Giri N, Jessop L, Myers T, et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 2011;25(1):11–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet. 2008;42:301–34.

    Article  PubMed  CAS  Google Scholar 

  69. Morrison SJ, Prowse KR, Ho P, Weissman IL. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity. 1996;5(3):207–16.

    Article  PubMed  CAS  Google Scholar 

  70. Chiu C-P, 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(2):239–48.

    Article  PubMed  CAS  Google Scholar 

  71. Harel I, Benayoun BA, Machado B, Singh PP, Hu CK, Pech MF, et al. A platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate. Cell. 2015;160(5):1013–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Meier B, Clejan I, Liu Y, Lowden M, Gartner A, Hodgkin J, et al. trt-1 is the Caenorhabditis elegans catalytic subunit of telomerase. PLoS Genet. 2006;2(2): e18.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Blasco MA, Lee H-W, Hande MP, Samper E, Lansdorp PM, DePinho RA, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997;91(1):25–34.

    Article  PubMed  CAS  Google Scholar 

  74. Lee HW, Blasco MA, Gottlieb GJ, Horner Ii JW, Greider CW, DePinho RA. Essential role of mouse telomerase in highly proliferative organs. Nature. 1998;392(6676):569–74.

    Article  PubMed  CAS  Google Scholar 

  75. Rudolph KL, Chang S, Lee H-W, Blasco M, Gottlieb GJ, Greider C, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999;96(5):701–12.

    Article  PubMed  CAS  Google Scholar 

  76. Herrera E, Samper E, Martín-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(11):2950–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Niewisch MR, Giri N, McReynolds LJ, Alsaggaf R, Bhala S, Alter BP, et al. Disease progression and clinical outcomes in telomere biology disorders. Blood. 2022;139(12):1807–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Alder JK, Armanios M. Telomere-mediated lung disease. Physiol Rev. 2022;102(4):1703–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Walne AJ, Dokal I. Advances in the understanding of dyskeratosis congenita. Br J Haematol. 2009;145(2):164–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Armanios M. The role of telomeres in human disease. Annu Rev Genomics Hum Genet. 2022;23:363–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Rossiello F, Jurk D, Passos JF, di d’Adda Fagagna F. Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol. 2022;24(2):135–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Knight S, Vulliamy T, Copplestone A, Gluckman E, Mason P, Dokal I. Dyskeratosis Congenita (DC) Registry: identification of new features of DC. Br J Haematol. 1998;103(4):990–6.

    Article  PubMed  CAS  Google Scholar 

  83. Alder JK, Cogan JD, Brown AF, Anderson CJ, Lawson WE, Lansdorp PM, et al. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genet. 2011;7(3):e1001352.

  84. Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci USA. 2005;102(44):15960–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Parry EM, Alder JK, Qi X, Chen JJ, Armanios M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood. 2011;117(21):5607–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Takai H, Jenkinson E, Kabir S, Babul-Hirji R, Najm-Tehrani N, Chitayat DA, et al. A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus. Genes Dev. 2016;30(7):812–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Kermasson L, Churikov D, Awad A, Smoom R, Lainey E, Touzot F, et al. Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects. Blood. 2022;139(16):2427–40.

    Article  PubMed  CAS  Google Scholar 

  88. Polvi A, Linnankivi T, Kivelä T, Herva R, Keating James P, Mäkitie O, et al. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Human Genet. 2012;90(3):540–9.

    Article  CAS  Google Scholar 

  89. Simon AJ, Lev A, Zhang Y, Weiss B, Rylova A, Eyal E, et al. Mutations in STN1 cause coats plus syndrome and are associated with genomic and telomere defects. J Exp Med. 2016;213(8):1429–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Holme H, Hossain U, Kirwan M, Walne A, Vulliamy T, Dokal I. Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. Br J Haematol. 2012;158(2):242–8.

    Article  PubMed  CAS  Google Scholar 

  91. Furutani E, Shimamura A. Genetic predisposition to MDS: diagnosis and management. Hematol Am Soc Hematol Educ Program. 2019;2019(1):110–9.

    Article  Google Scholar 

  92. Beerman I. Accumulation of DNA damage in the aged hematopoietic stem cell compartment. Semin Hematol. 2017;54(1):12–8.

    Article  PubMed  Google Scholar 

  93. Mollica L, Fleury I, Belisle C, Provost S, Roy DC, Busque L. No association between telomere length and blood cell counts in elderly individuals. J Gerontol A Biol Sci Med Sci. 2009;64(9):965–7.

    Article  PubMed  Google Scholar 

  94. Florian MC, Dörr K, Niebel A, Daria D, Schrezenmeier H, Rojewski M, et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell. 2012;10(5):520–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Ho TT, Warr MR, Adelman ER, Lansinger OM, Flach J, Verovskaya EV, et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature. 2017;543(7644):205–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Kramer A, Challen GA. The epigenetic basis of hematopoietic stem cell aging. Semin Hematol. 2017;54(1):19–24.

    Article  PubMed  Google Scholar 

  97. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C, et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia. 2013;27(6):1275–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Kaner J, Desai P, Mencia-Trinchant N, Guzman ML, Roboz GJ, Hassane DC. Clonal Hematopoiesis and Premalignant Diseases. Cold Spring Harb Perspect Med. 2020;10(4):a035675.

  100. Mitchell SR, Gopakumar J, Jaiswal S. Insights into clonal hematopoiesis and its relation to cancer risk. Curr Opin Genet Dev. 2021;66:63–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Belizaire R, Wong WJ, Robinette ML, Ebert BL. Clonal haematopoiesis and dysregulation of the immune system. Nat Rev Immunol. 2023;23(9):595–610.

    Article  PubMed  CAS  Google Scholar 

  102. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Ferrer A, Lasho T, Fernandez JA, Steinauer NP, Simon RA, Finke CM, et al. Patients with telomere biology disorders show context specific somatic mosaic states with high frequency of U2AF1 variants. Am J Hematol. 2023;98(12):E357–9.

    Article  PubMed  Google Scholar 

  104. Revy P, Kannengiesser C, Fischer A. Somatic genetic rescue in Mendelian haematopoietic diseases. Nat Rev Genet. 2019;20(10):582–98.

    Article  PubMed  CAS  Google Scholar 

  105. Revy P, Kannengiesser C, Fischer A. Somatic genetic rescue in Mendelian haematopoietic diseases. Nat Rev Genet. 2019;20(10):582–98.

    Article  PubMed  CAS  Google Scholar 

  106. Tsai FD, Lindsley RC. Clonal hematopoiesis in the inherited bone marrow failure syndromes. Blood. 2020;136(14):1615–22.

    PubMed  PubMed Central  Google Scholar 

  107. Perdigones N, Perin JC, Schiano I, Nicholas P, Biegel JA, Mason PJ, et al. Clonal hematopoiesis in patients with dyskeratosis congenita. Am J Hematol. 2016;91(12):1227–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Mangaonkar AA, Ferrer A, Pinto EVF, Cousin MA, Kuisle RJ, Klee EW, et al. Clinical correlates and treatment outcomes for patients with short telomere syndromes. Mayo Clin Proc. 2018;93(7):834–9.

    Article  PubMed  CAS  Google Scholar 

  109. Lee M, Roos P, Sharma N, Atalar M, Evans TA, Pellicore MJ, et al. Systematic computational identification of variants that activate exonic and intronic cryptic splice sites. Am J Human Genet. 2017;100(5):751–65.

    Article  CAS  Google Scholar 

  110. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–78.

    Article  PubMed  Google Scholar 

  111. Marioni RE, Shah S, McRae AF, Chen BH, Colicino E, Harris SE, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015;16(1):25.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the Center for Individualized Medicine, Mayo Clinic, for establishing the telomere biology disorders clinic and biobank and all the patients for their participation.

Author information

Authors and Affiliations

  1. Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA

    Terra Lasho & Mrinal M. Patnaik

Authors
  1. Terra Lasho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mrinal M. Patnaik
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.L. and M.P. wrote the main manuscript text and T.L. prepared figure 1.

Corresponding author

Correspondence to Mrinal M. Patnaik.

Ethics declarations

Ethics Approval

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Conflict of Interest

Dr. Lasho has nothing to disclose. Dr. Patnaik has received research funding from StemLine, Kura, Epigenetix, and Polaris and is currently on the advisory board for Center for Therapeutic Intervention (CTI).

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lasho, T., Patnaik, M.M. Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders. Curr Hematol Malig Rep 19, 35–44 (2024). https://doi.org/10.1007/s11899-023-00719-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-023-00719-2

Keywords

Search

Navigation