1932

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a state in which somatic mutations in hematopoietic stem cells lead to clonal expansion of blood cells in individuals without hematologic malignancy. The mutated genes, including , , , , , and , are also recurrently mutated in myeloid malignancies. Individuals with CHIP have an increased risk of developing a hematologic cancer. Moreover, individuals with CHIP have an elevated risk of all-cause mortality that is significantly attributable to cardiovascular disease, independent of traditional risk factors. The mechanism for this increased risk is likely linked to increased inflammation driven by mutated macrophages, in part through inflammasome activation. This has broadened our understanding of how chronic diseases are influenced by CHIP and of the mechanistic role of inflammation in these disorders.

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2022-04-11
2024-04-18
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Literature Cited

  1. Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N et al. 2018. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559:400–4
    [Google Scholar]
  2. Abplanalp WT, Cremer S, John D, Hoffmann J, Schuhmacher B et al. 2021. Clonal hematopoiesis—Driver DNMT3A mutations alter immune cells in heart failure. Circ. Res. 128:216–28
    [Google Scholar]
  3. Abplanalp WT, Mas-Peiro S, Cremer S, John D, Dimmeler S, Zeiher AM 2020. Association of clonal hematopoiesis of indeterminate potential with inflammatory gene expression in patients with severe degenerative aortic valve stenosis or chronic postischemic heart failure. JAMA Cardiol. 5:101170–75
    [Google Scholar]
  4. Adamson JW, Fialkow PJ, Murphy S, Prchal JF, Steinmann L. 1976. Polycythemia vera: stem-cell and probable clonal origin of the disease. N. Engl. J. Med. 295:913–16
    [Google Scholar]
  5. Agathocleous M, Meacham CE, Burgess RJ, Piskounova E, Zhao Z et al. 2017. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549:476–81
    [Google Scholar]
  6. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ et al. 2016. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–405
    [Google Scholar]
  7. Bick AG, Pirruccello JP, Griffin GK, Gupta N, Gabriel S et al. 2020a. Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation 141:124–31
    [Google Scholar]
  8. Bick AG, Weinstock JS, Nandakumar SK, Fulco CP, Bao EL et al. 2020b. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 586:763–68
    [Google Scholar]
  9. Bolton KL, Zehir A, Ptashkin RN, Patel M, Gupta D et al. 2020. The clinical management of clonal hematopoiesis: creation of a clonal hematopoiesis clinic. Hematol. Oncol. Clin. North Am. 34:357–67
    [Google Scholar]
  10. Bonnefond A, Skrobek B, Lobbens S, Eury E, Thuillier D et al. 2013. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat. Genet. 45:1040–43
    [Google Scholar]
  11. Bowman RL, Busque L, Levine RL. 2018. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22:157–70
    [Google Scholar]
  12. Brunner SF, Roberts ND, Wylie LA, Moore L, Aitken SJ et al. 2019. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature 574:538–42
    [Google Scholar]
  13. Busque L, Mio R, Mattioli J, Brais E, Blais N et al. 1996. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88:59–65
    [Google Scholar]
  14. Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S et al. 2012. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44:1179–81
    [Google Scholar]
  15. Challen GA, Goodell MA. 2020. Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood 136:1590–98
    [Google Scholar]
  16. Challen GA, Sun D, Jeong M, Luo M, Jelinek J et al. 2011. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44:23–31
    [Google Scholar]
  17. Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH et al. 2017. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170:1079–95.e20
    [Google Scholar]
  18. Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A et al. 2017. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21:374–82.e4
    [Google Scholar]
  19. Couronne L, Bastard C, Bernard OA. 2012. TET2 and DNMT3A mutations in human T-cell lymphoma. N. Engl. J. Med. 366:95–96
    [Google Scholar]
  20. Cremer S, Kirschbaum K, Berkowitsch A, John D, Kiefer K et al. 2020. Multiple somatic mutations for clonal hematopoiesis are associated with increased mortality in patients with chronic heart failure. Circ. Genom. Precis. Med. 13:e003003
    [Google Scholar]
  21. Dominguez PM, Ghamlouch H, Rosikiewicz W, Kumar P, Beguelin W et al. 2018. TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes B-cell lymphomagenesis. Cancer Discov. 8:1632–53
    [Google Scholar]
  22. Dorsheimer L, Assmus B, Rasper T, Ortmann CA, Abou-El-Ardat K et al. 2020. Hematopoietic alterations in chronic heart failure patients by somatic mutations leading to clonal hematopoiesis. Haematologica 105:e328–32
    [Google Scholar]
  23. Dorsheimer L, Assmus B, Rasper T, Ortmann CA, Ecke A et al. 2019. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol. 4:25–33
    [Google Scholar]
  24. Fey MF, Liechti-Gallati S, von Rohr A, Borisch B, Theilkas L et al. 1994. Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood 83:931–38
    [Google Scholar]
  25. Fidler TP, Xue C, Yalcinkaya M, Hardaway B, Abramowicz S et al. 2021. The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis. Nature 592:296–301
    [Google Scholar]
  26. Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA et al. 2018. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558:307–12
    [Google Scholar]
  27. Frick M, Chan W, Arends CM, Hablesreiter R, Halik A et al. 2019. Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation. J. Clin. Oncol. 37:375–85
    [Google Scholar]
  28. Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC et al. 2017. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842–47
    [Google Scholar]
  29. Fuster JJ, Zuriaga MA, Zorita V, MacLauchlan S, Polackal MN et al. 2020. TET2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity. Cell Rep. 33:108326
    [Google Scholar]
  30. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA et al. 2014. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371:2477–87
    [Google Scholar]
  31. Gibson CJ, Kennedy JA, Nikiforow S, Kuo FC, Alyea EP et al. 2017a. Donor-engrafted CHIP is common among stem cell transplant recipients with unexplained cytopenias. Blood 130:91–94
    [Google Scholar]
  32. Gibson CJ, Kim HT, Murdock HM, Hambley B, Zhao L et al. 2020. DNMT3A clonal hematopoiesis in older donors is associated with improved survival in recipients after allogeneic hematopoietic cell transplant. Blood 136:26–26
    [Google Scholar]
  33. Gibson CJ, Lindsley RC. 2020. Stem cell donors should not be screened for clonal hematopoiesis. Blood Adv. 4:789–92
    [Google Scholar]
  34. Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J et al. 2017b. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J. Clin. Oncol. 35:1598–605
    [Google Scholar]
  35. Gillis NK, Ball M, Zhang Q, Ma Z, Zhao Y et al. 2017. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 18:112–21
    [Google Scholar]
  36. Goodwin S, McPherson JD, McCombie WR. 2016. Coming of age: ten years of next-generation sequencing technologies. Nat. Rev. Genet. 17:333–51
    [Google Scholar]
  37. Guermouche H, Ravalet N, Gallay N, Deswarte C, Foucault A et al. 2020. High prevalence of clonal hematopoiesis in the blood and bone marrow of healthy volunteers. Blood Adv. 4:3550–57
    [Google Scholar]
  38. Gundestrup M, Klarskov Andersen M, Sveinbjornsdottir E, Rafnsson V, Storm HH, Pedersen-Bjergaard J 2000. Cytogenetics of myelodysplasia and acute myeloid leukaemia in aircrew and people treated with radiotherapy. Lancet 356:2158
    [Google Scholar]
  39. Heyde A, Rohde D, McAlpine CS, Zhang S, Hoyer FF et al. 2021. Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis. Cell 184:1348–61.e22
    [Google Scholar]
  40. Honigberg MC, Zekavat SM, Aragam K, Finneran P, Klarin D et al. 2019. Association of premature natural and surgical menopause with incident cardiovascular disease. JAMA 322:242411–21
    [Google Scholar]
  41. Honigberg MC, Zekavat SM, Niroula A, Griffin GK, Bick AG et al. 2021. Premature menopause, clonal hematopoiesis, and coronary artery disease in postmenopausal women. Circulation 143:410–23
    [Google Scholar]
  42. Hormaechea-Agulla D, Matatall KA, Le DT, Kain B, Long X et al. 2021. Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling. Cell Stem Cell 28:81428–42
    [Google Scholar]
  43. Hsu JI, Dayaram T, Tovy A, De Braekeleer E, Jeong M et al. 2018. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23:700–13.e6
    [Google Scholar]
  44. IL6R Genet. Consort. Emerg. Risk Factors Collab 2012. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 379:1205–13
    [Google Scholar]
  45. Jaiswal S, Ebert BL 2019. Clonal hematopoiesis in human aging and disease. Science 366:6465eaan4673
    [Google Scholar]
  46. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV et al. 2014. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371:2488–98
    [Google Scholar]
  47. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG et al. 2017. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377:111–21
    [Google Scholar]
  48. Jongen-Lavrencic M, Grob T, Hanekamp D, Kavelaars FG, Al Hinai A et al. 2018. Molecular minimal residual disease in acute myeloid leukemia. N. Engl. J. Med. 378:1189–99
    [Google Scholar]
  49. Kahn JD, Miller PG, Silver AJ, Sellar RS, Bhatt S et al. 2018. PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132:1095–105
    [Google Scholar]
  50. Kwok B, Hall JM, Witte JS, Xu Y, Reddy P et al. 2015. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 126:2355–61
    [Google Scholar]
  51. Lee-Six H, Obro NF, Shepherd MS, Grossmann S, Dawson K et al. 2018. Population dynamics of normal human blood inferred from somatic mutations. Nature 561:473–78
    [Google Scholar]
  52. Lee-Six H, Olafsson S, Ellis P, Osborne RJ, Sanders MA et al. 2019. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574:532–37
    [Google Scholar]
  53. Levine ME, Lu AT, Chen BH, Hernandez DG, Singleton AB et al. 2016. Menopause accelerates biological aging. PNAS 113:9327–32
    [Google Scholar]
  54. Libby P, Sidlow R, Lin AE, Gupta D, Jones LW et al. 2019. Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week. J. Am. Coll. Cardiol. 74:567–77
    [Google Scholar]
  55. Malcovati L, Galli A, Travaglino E, Ambaglio I, Rizzo E et al. 2017. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 129:3371–78
    [Google Scholar]
  56. Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F et al. 2018. Somatic mutant clones colonize the human esophagus with age. Science 362:911–17
    [Google Scholar]
  57. Martincorena I, Raine KM, Gerstung M, Dawson KJ, Haase K et al. 2017. Universal patterns of selection in cancer and somatic tissues. Cell 171:1029–41.e21
    [Google Scholar]
  58. Mas-Peiro S, Hoffmann J, Fichtlscherer S, Dorsheimer L, Rieger MA et al. 2019. Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. Eur. Heart J. 41:8933–39
    [Google Scholar]
  59. McCarthy M, Raval AP. 2020. The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease. J. Neuroinflamm. 17:317
    [Google Scholar]
  60. Miles LA, Bowman RL, Merlinsky TR, Csete IS, Ooi AT et al. 2020. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 587:477–82
    [Google Scholar]
  61. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D et al. 2011. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20:11–24
    [Google Scholar]
  62. Mouhieddine TH, Sperling AS, Redd R, Park J, Leventhal M et al. 2020. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant. Nat. Commun. 11:2996
    [Google Scholar]
  63. Mouly E, Ghamlouch H, Della-Valle V, Scourzic L, Quivoron C et al. 2018. B-cell tumor development in Tet2-deficient mice. Blood Adv. 2:703–14
    [Google Scholar]
  64. Muka T, Oliver-Williams C, Kunutsor S, Laven JS, Fauser BC et al. 2016. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol. 1:767–76
    [Google Scholar]
  65. Muto H, Sakata-Yanagimoto M, Nagae G, Shiozawa Y, Miyake Y et al. 2014. Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice. Blood Cancer J. 4:e264
    [Google Scholar]
  66. Nishanth G, Wolleschak D, Fahldieck C, Fischer T, Mullally A et al. 2017. Gain of function in Jak2V617F-positive T-cells. Leukemia 31:1000–3
    [Google Scholar]
  67. Orlanski S, Labi V, Reizel Y, Spiro A, Lichtenstein M et al. 2016. Tissue-specific DNA demethylation is required for proper B-cell differentiation and function. PNAS 113:5018–23
    [Google Scholar]
  68. Otto CM, Prendergast B. 2014. Aortic-valve stenosis—from patients at risk to severe valve obstruction. N. Engl. J. Med. 371:744–56
    [Google Scholar]
  69. Pascual-Figal DA, Bayes-Genis A, Diez-Diez M, Hernandez-Vicente A, Vazquez-Andres D 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]
  70. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C. 2002. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 99:1909–12
    [Google Scholar]
  71. Ratain MJ, Rowley JD. 1992. Therapy-related acute myeloid leukemia secondary to inhibitors of topoisomerase II: from the bedside to the target genes. Ann. Oncol. 3:107–11
    [Google Scholar]
  72. Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R et al. 2014. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat. Genet. 46:171–75
    [Google Scholar]
  73. Sano S, Oshima K, Wang Y, Katanasaka Y, Sano M, Walsh K. 2018a. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. Circ. Res. 123:335–41
    [Google Scholar]
  74. Sano S, Oshima K, Wang Y, MacLauchlan S, Katanasaka Y et al. 2018b. 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]
  75. Seita J, Weissman IL. 2010. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip. Rev. Syst. Biol. Med. 2:640–53
    [Google Scholar]
  76. Shi K, Zhao W, Chen Y, Ho WT, Yang P, Zhao ZJ 2014. Cardiac hypertrophy associated with myeloproliferative neoplasms in JAK2V617F transgenic mice. J. Hematol. Oncol. 7:25
    [Google Scholar]
  77. Sidlow R, Lin AE, Gupta D, Bolton KL, Steensma DP et al. 2020. The clinical challenge of clonal hematopoiesis, a newly recognized cardiovascular risk factor. JAMA Cardiol. 5:8958–61
    [Google Scholar]
  78. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA et al. 2015. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126:9–16
    [Google Scholar]
  79. Steensma DP, Bolton KL. 2020. What to tell your patient with clonal hematopoiesis and why: insights from 2 specialized clinics. Blood 136:1623–31
    [Google Scholar]
  80. Steensma DP, Ebert BL. 2020. Clonal hematopoiesis as a model for premalignant changes during aging. Exp. Hematol. 83:48–56
    [Google Scholar]
  81. Takahashi K, Wang F, Kantarjian H, Doss D, Khanna K et al. 2017. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 18:100–11
    [Google Scholar]
  82. Van Egeren D, Escabi J, Nguyen M, Liu S, Reilly CR et al. 2021. Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in myeloproliferative neoplasms. Cell Stem Cell 28:514–23.e9
    [Google Scholar]
  83. Wang W, Liu W, Fidler T, Wang Y, Tang Y et al. 2018. Macrophage inflammation, erythrophagocytosis, and accelerated atherosclerosis in Jak2V617F mice. Circ. Res. 123:e35–47
    [Google Scholar]
  84. Wang Y, Sano S, Yura Y, Ke Z, Sano M et al. 2020. Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction. JCI Insight 5:6e135204
    [Google Scholar]
  85. Williams N, Lee J, Moore L, Baxter JE, Hewinson J et al. 2020. Driver mutation acquisition in utero and childhood followed by lifelong clonal evolution underlie myeloproliferative neoplasms. Blood 136:LBA-1
    [Google Scholar]
  86. Wolach O, Sellar RS, Martinod K, Cherpokova D, McConkey M et al. 2018. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl. Med. 10:436eaan8292
    [Google Scholar]
  87. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ et al. 2014. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20:1472–78
    [Google Scholar]
  88. Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K et al. 2015. Somatic mutations and clonal hematopoiesis in aplastic anemia. N. Engl. J. Med. 373:35–47
    [Google Scholar]
  89. Young AL, Challen GA, Birmann BM, Druley TE. 2016. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7:12484
    [Google Scholar]
  90. Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT et al. 2017. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130:742–52
    [Google Scholar]
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