1932

Abstract

Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-042921-112347
2023-01-27
2024-06-13
Loading full text...

Full text loading...

/deliver/fulltext/med/74/1/annurev-med-042921-112347.html?itemId=/content/journals/10.1146/annurev-med-042921-112347&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Jaiswal S, Fontanillas P, Flannick J et al. 2014. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371:2488–98
    [Google Scholar]
  2. 2.
    Natarajan P, Siddhartha J, Kathiresan S 2018. Clonal hematopoiesis: somatic mutations in blood cells and atherosclerosis. Circ. Genom. Precis. Med. 11:e001926
    [Google Scholar]
  3. 3.
    Jaiswal S, Ebert BL. 2019. Clonal hematopoiesis in human aging and disease. Science 366:eaan4673
    [Google Scholar]
  4. 4.
    Steensma DP, Bejar R, Jaiswal S et al. 2015. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126:9–16
    [Google Scholar]
  5. 5.
    Genovese G, Kähler AK, Handsaker RE et al. 2014. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371:2477–87
    [Google Scholar]
  6. 6.
    McKerrell T, Park N, Moreno T et al. 2015. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 10:1239–45
    [Google Scholar]
  7. 7.
    Bick AG, Weinstock JS, Nandakumar SK et al. 2020. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 586:763–68
    [Google Scholar]
  8. 8.
    Champion KM, Gilbert JGR, Asimakopoulos FA et al. 1997. Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. Br. J. Haematol. 97:920–26
    [Google Scholar]
  9. 9.
    Busque L, Mio R, Mattioli J et al. 1996. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88:59–65
    [Google Scholar]
  10. 10.
    Busque L, Patel JP, Figueroa M et al. 2012. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44:1179–81
    [Google Scholar]
  11. 11.
    Abelson S, Collord G, Ng SWK et al. 2018. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559:400–4
    [Google Scholar]
  12. 12.
    Desai P, Mencia-Trinchant N, Savenkov O et al. 2018. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat. Med. 24:1015–23
    [Google Scholar]
  13. 13.
    Jacobs KB, Yeager M, Zhou W et al. 2012. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44:651–58
    [Google Scholar]
  14. 14.
    Laurie CC, Laurie CA, Rice K et al. 2012. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44:642–50
    [Google Scholar]
  15. 15.
    Niroula A, Sekar A, Murakami MA et al. 2021. Distinction of lymphoid and myeloid clonal hematopoiesis. Nat. Med. 27:1921–27
    [Google Scholar]
  16. 16.
    Ryunosuke S. 2021. Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis. Nat. Med. 27:1239–49
    [Google Scholar]
  17. 17.
    Coombs CC, Zehir A, Devlin SM et al. 2017. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome. Cell Stem Cell 21:374–82.e4
    [Google Scholar]
  18. 18.
    Kahn JD, Miller PG, Silver AJ et al. 2018. PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132:1095–105
    [Google Scholar]
  19. 19.
    Bolton KL, Ptashkin RN, Gao T et al. 2020. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat. Genet. 52:1219–26
    [Google Scholar]
  20. 20.
    Park SJ, Bejar R. 2020. Clonal hematopoiesis in cancer. Exp. Hematol. 83:105–12
    [Google Scholar]
  21. 21.
    Kleppe M, Comen E, Wen HY et al. 2015. Somatic mutations in leukocytes infiltrating primary breast cancers. npj Breast Cancer 1:15005
    [Google Scholar]
  22. 22.
    Jaiswal S, Natarajan P, Silver AJ et al. 2017. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377:111–21
    [Google Scholar]
  23. 23.
    Bhattacharya R, Zekavat SM, Haessler J et al. 2022. Clonal hematopoiesis is associated with higher risk of stroke. Stroke 29:788–97
    [Google Scholar]
  24. 24.
    Bick AG, Pirruccello JP, Griffin GK et al. 2020. Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation 141:124–31
    [Google Scholar]
  25. 25.
    Kessler MD, Damask A, O'Keeffe S et al. 2022. Exome sequencing of 628,388 individuals identifies common and rare variant associations with clonal hematopoiesis phenotypes. medRxiv 2021.12.29.21268342
    [Google Scholar]
  26. 26.
    Kar SP, Quiros PM, Gu M et al. 2022. Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis. Nat. Genet. 54:1155–66
    [Google Scholar]
  27. 27.
    Fry A, Littlejohns TJ, Sudlow C et al. 2017. Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population. Am. J. Epidemiol. 186:1026–34
    [Google Scholar]
  28. 28.
    Fuster JJ, MacLauchlan S, Zuriaga MA et al. 2017. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842–47
    [Google Scholar]
  29. 29.
    Rauch PJ, Silver AJ, Gopakumar J et al. 2018. Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and convergent macrophage phenotypes in mice. Blood 132:745
    [Google Scholar]
  30. 30.
    Wolach O, Sellar RS, Martinod K et al. 2018. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl. Med. 10:eaan8292
    [Google Scholar]
  31. 31.
    Fidler TP, Xue C, Yalcinkaya M et al. 2021. The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis. Nature 592:296–301
    [Google Scholar]
  32. 32.
    Dorsheimer L, Assmus B, Rasper T et al. 2019. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol. 4:32–40
    [Google Scholar]
  33. 33.
    Pascual-Figal DA, Bayes-Genis A, Díez-Díez M et al. 2021. Clonal hematopoiesis and risk of progression of heart failure with reduced left ventricular ejection fraction. J. Am. Coll. Cardiol. 77:1747–59
    [Google Scholar]
  34. 34.
    Sano S, Oshima K, Wang Y et al. 2018. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71:875–86
    [Google Scholar]
  35. 35.
    Sano S, Wang Y, Walsh K. 2018. Clonal hematopoiesis and its impact on cardiovascular disease. Circ. J. 83:2–11
    [Google Scholar]
  36. 36.
    Ridker PM, Everett BM, Thuren T et al. 2017. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377:1119–31
    [Google Scholar]
  37. 37.
    Svensson EC. TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol. 7:521–28
    [Google Scholar]
  38. 38.
    Miller PG, Qiao D, Rojas-Quintero J et al. 2022. Association of clonal hematopoiesis with chronic obstructive pulmonary disease. Blood 139:357–68
    [Google Scholar]
  39. 39.
    Kim PG, Niroula A, Shkolnik V et al. 2021. Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis. J. Exp. Med. 218:e20211872
    [Google Scholar]
  40. 40.
    Bouzid H, Belk JA, Jan M et al. 2021. Clonal hematopoiesis is associated with protection from Alzheimer's disease. medRxiv 2021.12.10.21267552
    [Google Scholar]
  41. 41.
    Zink F, Stacey SN, Norddahl GL et al. 2017. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130:742–52
    [Google Scholar]
  42. 42.
    Taliun D, Harris DN, Kessler MD et al. 2021. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590:290–99
    [Google Scholar]
  43. 43.
    Backman JD, Li AH, Marcketta A et al. 2021. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature 599:628–34
    [Google Scholar]
  44. 44.
    Wright WE, Piatyszek MA, Rainey WE et al. 1996. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18:173–79
    [Google Scholar]
  45. 45.
    Shay JW, Wright WE. 2019. Telomeres and telomerase: three decades of progress. Nat. Rev. Genet. 20:299–309
    [Google Scholar]
  46. 46.
    Hastie ND, Dempster M, Dunlop MG et al. 1990. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346:866–68
    [Google Scholar]
  47. 47.
    Chiba K, Lorbeer FK, Shain AH et al. 2017. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science 357:1416–20
    [Google Scholar]
  48. 48.
    Sanderson E, Glymour MM, Holmes MV et al. 2022. Mendelian randomization. Nat. Rev. Methods Primers 2:6
    [Google Scholar]
  49. 49.
    Nakao T, Bick AG, Taub MA et al. 2022. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential. Sci. Adv. 8:eabl6579
    [Google Scholar]
  50. 50.
    Ray Chaudhuri A, Nussenzweig A 2017. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 18:610–21
    [Google Scholar]
  51. 51.
    Farmer H, McCabe N, Lord CJ et al. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21
    [Google Scholar]
  52. 52.
    Medina R, van der Deen M, Miele-Chamberland A et al. 2007. The HiNF-P/p220NPAT cell cycle signaling pathway controls nonhistone target genes. Cancer Res. 67:10334–42
    [Google Scholar]
  53. 53.
    Forde S, Tye BJ, Newey SE et al. 2007. Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells. Blood 109:1825–33
    [Google Scholar]
  54. 54.
    Losada A, Hirano T. 2005. Dynamic molecular linkers of the genome: the first decade of SMC proteins. Genes Dev. 19:1269–87
    [Google Scholar]
  55. 55.
    He H, Zheng C, Tang Y. 2021. Overexpression of SMC4 predicts a poor prognosis in cervical cancer and facilitates cancer cell malignancy phenotype by activating NF-κB pathway. Hum. Cell 34:1888–98
    [Google Scholar]
  56. 56.
    Thompson DJ, Genovese G, Halvardson J et al. 2019. Genetic predisposition to mosaic Y chromosome loss in blood. Nature 575:652–57
    [Google Scholar]
  57. 57.
    Zhou W, Machiela MJ, Freedman ND et al. 2016. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat. Genet. 48:563–68
    [Google Scholar]
  58. 58.
    Okano M, Bell DW, Haber DA, Li E 1999. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–57
    [Google Scholar]
  59. 59.
    Kohli RM, Zhang Y. 2013. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502:472–79
    [Google Scholar]
  60. 60.
    Božić T, Frobel J, Raic A et al. 2018. Variants of DNMT3A cause transcript-specific DNA methylation patterns and affect hematopoiesis. Life Sci. Alliance 1:e201800153
    [Google Scholar]
  61. 61.
    Zhang X, Su J, Jeong M et al. 2016. DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nat. Genet. 48:1014–23
    [Google Scholar]
  62. 62.
    Buscarlet M, Provost S, Zada YF et al. 2017. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130:753–62
    [Google Scholar]
  63. 63.
    Fraga MF, Esteller M. 2007. Epigenetics and aging: the targets and the marks. Trends Genet. 23:413–18
    [Google Scholar]
  64. 64.
    Hannum G, Guinney J, Zhao L et al. 2013. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell 49:359–67
    [Google Scholar]
  65. 65.
    Horvath S, Oshima J, Martin GM et al. 2018. Epigenetic clock for skin and blood cells applied to Hutchinson Gilford progeria syndrome and ex vivo studies. Aging 10:1758–75
    [Google Scholar]
  66. 66.
    Horvath S. 2013. DNA methylation age of human tissues and cell types. Genome Biol. 14:R115
    [Google Scholar]
  67. 67.
    Levine ME, Lu AT, Quach A et al. 2018. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10:573–91
    [Google Scholar]
  68. 68.
    Lu AT, Quach A, Wilson JG et al. 2019. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11:303–27
    [Google Scholar]
  69. 69.
    Robertson NA, Hillary RF, McCartney DL et al. 2019. Age-related clonal haemopoiesis is associated with increased epigenetic age. Curr. Biol. 29:R786–87
    [Google Scholar]
  70. 70.
    Nachun D, Lu AT, Bick AG et al. 2021. Clonal hematopoiesis associated with epigenetic aging and clinical outcomes. Aging Cell 20:e13366
    [Google Scholar]
  71. 71.
    Mitchell E, Chapman MS, Williams N et al. 2021. Clonal dynamics of haematopoiesis across the human lifespan. bioRxiv 2021.08.16.456475
    [Google Scholar]
  72. 72.
    Watson CJ, Papula AL, Poon GYP et al. 2020. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science 367:1449–54
    [Google Scholar]
  73. 73.
    Lee-Six H, Øbro NF, Shepherd MS et al. 2018. Population dynamics of normal human blood inferred from somatic mutations. Nature 561:473–78
    [Google Scholar]
  74. 74.
    Dharan NJ, Yeh P, Bloch M et al. 2021. HIV is associated with an increased risk of age-related clonal hematopoiesis among older adults. Nat. Med. 27:1006–11
    [Google Scholar]
  75. 75.
    Meisel M, Hinterleitner R, Pacis A et al. 2018. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557:580–84
    [Google Scholar]
  76. 76.
    Wong TN, Ramsingh G, Young AL et al. 2015. The role of TP53 mutations in the origin and evolution of therapy-related AML. Nature 518:552–55
    [Google Scholar]
  77. 77.
    Williams N, Lee J, Mitchell E et al. 2022. Life histories of myeloproliferative neoplasms inferred from phylogenies. Nature 602:162–68
    [Google Scholar]
  78. 78.
    Abelson S, Collord G, Ng SWK et al. 2018. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559:400–4
    [Google Scholar]
  79. 79.
    Fabre MA, de Almeida JG, Fiorillo E et al. 2021. The longitudinal dynamics and natural history of clonal haematopoiesis. bioRxiv 2021.08.12.455048
    [Google Scholar]
  80. 80.
    Osorio FG, Rosendahl Huber A, Oka R et al. 2018. Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis. Cell Rep. 25:2308–16.e4
    [Google Scholar]
  81. 81.
    Weinstock JS, Gopakumar J, Burugula BB et al. 2021. Clonal hematopoiesis is driven by aberrant activation of TCL1A. bioRxiv 2021.12.10.471810
    [Google Scholar]
  82. 82.
    Robertson NA, Latorre-Crespo E, Terradas-Terradas M et al. 2021. Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects. bioRxiv 2021.05.27.446006
    [Google Scholar]
/content/journals/10.1146/annurev-med-042921-112347
Loading
/content/journals/10.1146/annurev-med-042921-112347
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error