Somatic mutations and clonal hematopoiesis: Unexpected potential new drivers of age-related cardiovascular disease

Circulation Research

Volumn 122, Issue 3, 2018, Pages 523-532

  Fuster, José J ^a   Walsh, Kenneth ^a  

^a BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Aging; Atherosclerosis; Cardiovascular disease; CHIP; Inflammation; Risk factors

Indexed keywords

DNA METHYLTRANSFERASE 3A; DNA (CYTOSINE 5) METHYLTRANSFERASE; DNA BINDING PROTEIN; JAK2 PROTEIN, HUMAN; JANUS KINASE 2; ONCOPROTEIN; TET2 PROTEIN, HUMAN; TET2 PROTEIN, MOUSE;

AGE; AGING; ASXL1 GENE; ATHEROSCLEROSIS; BONE MARROW CELL; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CELL THERAPY; CLONAL HEMATOPOIESIS; DISEASE ASSOCIATION; DNMT3A GENE; EVIDENCE BASED MEDICINE; GENE; GENETIC ASSOCIATION; GENETIC VARIABILITY; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HUMAN; MUTATIONAL ANALYSIS; NONHUMAN; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; SOMATIC MUTATION; TET2 GENE; AGED; ANIMAL; BONE MARROW TRANSPLANTATION; CAUSALITY; CELL CLONE; DEFICIENCY; GENETIC ASSOCIATION STUDY; GENETICS; HEMATOLOGIC DISEASE; MOUSE; MUTATION; PATHOLOGY; PERSONALIZED MEDICINE; PHYSIOLOGY; POPULATION DYNAMICS; RISK FACTOR; TUMOR GENE;

AGED; AGING; ANIMALS; ATHEROSCLEROSIS; BONE MARROW TRANSPLANTATION; CARDIOVASCULAR DISEASES; CAUSALITY; CLONE CELLS; DNA (CYTOSINE-5-)-METHYLTRANSFERASES; DNA-BINDING PROTEINS; GENES, NEOPLASM; GENETIC ASSOCIATION STUDIES; HEMATOLOGIC NEOPLASMS; HEMATOPOIESIS; HEMATOPOIETIC STEM CELLS; HUMANS; JANUS KINASE 2; MICE; MUTATION; POPULATION DYNAMICS; PRECISION MEDICINE; PROTO-ONCOGENE PROTEINS; RISK FACTORS;

EID: 85047732897     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.117.312115     Document Type: Review

References (117)

1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459-1544. doi: 10.1016/S0140-6736(16)31012-1.
2. Sniderman AD, Furberg CD. Age as a modifiable risk factor for cardiovascular disease. Lancet. 2008;371:1547-1549. doi: 10.1016/S0140-6736(08)60313-X.
3. D'Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB. General cardiovascular risk profile for use in primary care: The Framingham Heart Study. Circulation. 2008;117:743-753. doi: 10.1161/CIRCULATIONAHA.107.699579.
4. Kannel WB, Vasan RS. Is age really a non-modifiable cardiovascular risk factor? Am J Cardiol. 2009;104:1307-1310. doi: 10.1016/j. amjcard.2009.06.051.
5. Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, Brener SJ, Ellis SG, Lincoff AM, Topol EJ. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003;290:898-904. doi: 10.1001/jama.290.7.898.
6. Baber U, Mehran R, Sartori S, Schoos MM, Sillesen H, Muntendam P, Garcia MJ, Gregson J, Pocock S, Falk E, Fuster V. Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: The BioImage study. J Am Coll Cardiol. 2015;65:1065-1074. doi: 10.1016/j.jacc.2015.01.017.
7. Fernández-Friera L, Peñalvo JL, Fernández-Ortiz A, et al. Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-Aged cohort: The PESA (Progression of Early Subclinical Atherosclerosis) Study. Circulation. 2015;131:2104-2113. doi: 10.1161/CIRCULATIONAHA.114.014310.
8. Laclaustra M, Casasnovas JA, Fernández-Ortiz A, Fuster V, León-Latre M, Jiménez-Borreguero LJ, Pocovi M, Hurtado-Roca Y, Ordovas JM, Jarauta E, Guallar E, Ibañez B, Civeira F. Femoral and carotid subclinical atherosclerosis association with risk factors and coronary calcium: The AWHS Study. J Am Coll Cardiol. 2016;67:1263-1274. doi: 10.1016/j. jacc.2015.12.056.
9. Fernández-Friera L, Fuster V, López-Melgar B, Oliva B, García-Ruiz JM, Mendiguren J, Bueno H, Pocock S, Ibáñez B, Fernández-Ortiz A, Sanz J. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol. 2017;70:2979-2991. doi: 10.1016/j.jacc.2017.10.024.
10. Gränsbo K, Almgren P, Nilsson PM, Hedblad B, Engström G, Melander O. Risk factor exposure in individuals free from cardiovascular disease differs according to age at first myocardial infarction. Eur Heart J. 2016;37:1977-1981. doi: 10.1093/eurheartj/ehw026.
11. Sniderman AD, Islam S, McQueen M, Pencina M, Furberg CD, Thanassoulis G, Yusuf S. Age and cardiovascular risk attributable to apolipoprotein B, low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. J Am Heart Assoc. 2016;5:e003665.
12. Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: A meta-Analysis of individual data from 61 prospective studies with 55, 000 vascular deaths. Lancet. 2007;370:1829-1839. doi: 10.1016/S0140-6736(07)61778-4.
13. Nicholls SJ, Ballantyne CM, Barter PJ, Chapman MJ, Erbel RM, Libby P, Raichlen JS, Uno K, Borgman M, Wolski K, Nissen SE. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078-2087. doi: 10.1056/NEJMoa1110874.
14. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-Treated patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016;316:2373-2384. doi: 10.1001/jama.2016.16951.
15. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R; Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-Analysis of data from 170, 000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681. doi: 10.1016/S0140-6736(10)61350-5.
16. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722. doi: 10.1056/NEJMoa1615664.
17. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937-952. doi: 10.1016/S0140-6736(04)17018-9.
18. Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet. 2017;18:331-344. doi: 10.1038/nrg.2016.160.
19. O'Donnell CJ, Nabel EG. Genomics of cardiovascular disease. N Engl J Med. 2011;365:2098-2109. doi: 10.1056/NEJMra1105239.
20. Poduri A, Evrony GD, Cai X, Walsh CA. Somatic mutation, genomic variation, and neurological disease. Science. 2013;341:1237758. doi: 10.1126/science.1237758.
21. Lodato MA, Woodworth MB, Lee S, Evrony GD, Mehta BK, Karger A, Lee S, Chittenden TW, D'Gama AM, Cai X, Luquette LJ, Lee E, Park PJ, Walsh CA. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science. 2015;350:94-98. doi: 10.1126/science. aab1785.
22. Ju YS, Martincorena I, Gerstung M, et al. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature. 2017;543:714-718. doi: 10.1038/nature21703.
23. Martincorena I, Roshan A, Gerstung M, et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 2015;348:880-886.
24. Welch JS, Ley TJ, Link DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150:264-278. doi: 10.1016/j. cell.2012.06.023.
25. Forsberg LA, Gisselsson D, Dumanski JP. Mosaicism in health and disease-clones picking up speed. Nat Rev Genet. 2017;18:128-142. doi: 10.1038/nrg.2016.145.
26. Vijg J. Somatic mutations, genome mosaicism, cancer and aging. Curr Opin Genet Dev. 2014;26:141-149. doi: 10.1016/j.gde.2014.04.002.
27. Fey MF, Liechti-Gallati S, von Rohr A, Borisch B, Theilkäs L, Schneider V, Oestreicher M, Nagel S, Ziemiecki A, Tobler A. Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood. 1994;83:931-938.
28. Gale RE, Fielding AK, Harrison CN, Linch DC. Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age. Br J Haematol. 1997;98:512-519.
29. Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, Maragh M, Gilliland DG. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood. 1996;88:59-65.
30. Shlush LI. Age related clonal hematopoiesis (ARCH) [published online ahead of print November 15, 2017]. Blood. doi: 10.1182/blood-2017-07-746453. http://www.bloodjournal.org/content/early/2017/11/15/blood-2017-07-746453.long
31. Zink F, Stacey SN, Norddahl GL, et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 2017;130:742-752. doi: 10.1182/blood-2017-02-769869.
32. Buscarlet M, Provost S, Zada YF, Barhdadi A, Bourgoin V, Lépine G, Mollica L, Szuber N, Dubé MP, Busque L. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood. 2017;130:753-762. doi: 10.1182/blood-2017-04-777029.
33. McKerrell T, Park N, Moreno T, et al; Understanding Society Scientific Group. Leukemia-Associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015;10:1239-1245. doi: 10.1016/j.celrep.2015.02.005.
34. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472-1478. doi: 10.1038/nm.3733.
35. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-2498. doi: 10.1056/NEJMoa1408617.
36. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477-2487. doi: 10.1056/NEJMoa1409405.
37. Acuna-Hidalgo R, Sengul H, Steehouwer M, van de Vorst M, Vermeulen SH, Kiemeney LALM, Veltman JA, Gilissen C, Hoischen A. Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis-Associated mutations throughout adult life. Am J Hum Genet. 2017;101:50-64. doi: 10.1016/j.ajhg.2017.05.013.
38. Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44:1179-1181. doi: 10.1038/ng.2413.
39. Goodell MA, Rando TA. Stem cells and healthy aging. Science. 2015;350:1199-1204. doi: 10.1126/science.aab3388.
40. Holstege H, Pfeiffer W, Sie D, et al. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res. 2014;24:733-742. doi: 10.1101/gr.162131.113.
41. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, Ebert BL. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9-16. doi: 10.1182/blood-2015-03-631747.
42. Bejar R. CHIP, ICUS, CCUS and other four-letter words. Leukemia. 2017;31:1869-1871. doi: 10.1038/leu.2017.181.
43. Bonnefond A, Skrobek B, Lobbens S, Eury E, Thuillier D, Cauchi S, Lantieri O, Balkau B, Riboli E, Marre M, Charpentier G, Yengo L, Froguel P. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat Genet. 2013;45:1040-1043. doi: 10.1038/ng.2700.
44. Forsberg LA, Rasi C, Razzaghian HR, et al. Age-related somatic structural changes in the nuclear genome of human blood cells. Am J Hum Genet. 2012;90:217-228. doi: 10.1016/j.ajhg.2011.12.009.
45. Jacobs KB, Yeager M, Zhou W, et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet. 2012;44:651-658. doi: 10.1038/ng.2270.
46. Laurie CC, Laurie CA, Rice K, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet. 2012;44:642-650. doi: 10.1038/ng.2271.
47. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111-121. doi: 10.1056/NEJMoa1701719.
48. Challen GA, Sun D, Jeong M, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2011;44:23-31. doi: 10.1038/ng.1009.
49. Guryanova OA, Lieu YK, Garrett-Bakelman FE, et al. Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells. Leukemia. 2016;30:1133-1142. doi: 10.1038/leu.2015.358.
50. Fisher CL, Pineault N, Brookes C, Helgason CD, Ohta H, Bodner C, Hess JL, Humphries RK, Brock HW. Loss-of-function additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood. 2010;115:38-46. doi: 10.1182/blood-2009-07-230698.
51. Abdel-Wahab O, Gao J, Adli M, et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med. 2013;210:2641-2659. doi: 10.1084/jem.20131141.
52. Wang J, Li Z, He Y, et al. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice. Blood. 2014;123:541-553. doi: 10.1182/blood-2013-05-500272.
53. Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A. Ten-eleventranslocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci USA. 2011;108:14566-14571.
54. Moran-Crusio K, Reavie L, Shih A, et al. TET2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20:11-24. doi: 10.1016/j.ccr.2011.06.001.
55. Quivoron C, Couronné L, Della Valle V, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20:25-38. doi: 10.1016/j.ccr.2011.06.003.
56. De T, Prabhakar P, Nagaraja D, Christopher R. Janus kinase (JAK) 2 V617F mutation in Asian Indians with cerebral venous thrombosis and without overt myeloproliferative disorders. J Neurol Sci. 2012;323:178-182. doi: 10.1016/j.jns.2012.09.012.
57. De Stefano V, Fiorini A, Rossi E, Za T, Farina G, Chiusolo P, Sica S, Leone G. Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost. 2007;5:708-714. doi: 10.1111/j.1538-7836.2007.02424.x.
58. Muendlein A, Gasser K, Kinz E, Stark N, Leiherer A, Rein P, Saely CH, Grallert H, Peters A, Drexel H, Lang AH. Evaluation of the prevalence and prospective clinical impact of the JAK2 V617F mutation in coronary patients. Am J Hematol. 2014;89:295-301. doi: 10.1002/ajh.23632.
59. Muendlein A, Kinz E, Gasser K, Leiherer A, Rein P, Saely CH, Grallert H, Peters A, Fraunberger P, Drexel H, Lang AH. Occurrence of the JAK2 V617F mutation in patients with peripheral arterial disease. Am J Hematol. 2015;90:E17-E21. doi: 10.1002/ajh.23874.
60. Hasselbalch HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood. 2012;119:3219-3225. doi: 10.1182/blood-2011-11-394775.
61. Li J, Spensberger D, Ahn JS, et al. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617Fpositive essential thrombocythemia. Blood. 2010;116:1528-1538. doi: 10.1182/blood-2009-12-259747.
62. Mullally A, Lane SW, Ball B, et al. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell. 2010;17:584-596. doi: 10.1016/j.ccr.2010.05.015.
63. Akada H, Yan D, Zou H, Fiering S, Hutchison RE, Mohi MG. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. Blood. 2010;115:3589-3597. doi: 10.1182/blood-2009-04-215848.
64. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333:1300-1303. doi: 10.1126/science.1210597.
65. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468:839-843. doi: 10.1038/nature09586.
66. He YF, Li BZ, Li Z, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011;333:1303-1307. doi: 10.1126/science.1210944.
67. Zhang Q, Zhao K, Shen Q, et al. TET2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015;525:389-393. doi: 10.1038/nature15252.
68. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, Yang FC, Xu M. Deletion of TET2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011;118:4509-4518. doi: 10.1182/blood-2010-12-325241.
69. Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 2000;7:273-281.
70. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355:842-847. doi: 10.1126/science.aag1381.
71. Cull AH, Snetsinger B, Buckstein R, Wells RA, Rauh MJ. TET2 restrains inflammatory gene expression in macrophages. Exp Hematol. 2017;55:56. e13-70.e13. doi: 10.1016/j.exphem.2017.08.001.
72. Manson JC, Symons JA, Di Giovine FS, Poole S, Duff GW. Autoregulation of interleukin 1 production. Eur J Immunol. 1989;19:261-265. doi: 10.1002/eji.1830190207.
73. Hiscott J, Marois J, Garoufalis J, D'Addario M, Roulston A, Kwan I, Pepin N, Lacoste J, Nguyen H, Bensi G. Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol Cell Biol. 1993;13:6231-6240.
74. Warner SJ, Auger KR, Libby P. Interleukin 1 induces interleukin 1. II. Recombinant human interleukin 1 induces interleukin 1 production by adult human vascular endothelial cells. J Immunol. 1987;139:1911-1917.
75. Dinarello CA, Ikejima T, Warner SJ, Orencole SF, Lonnemann G, Cannon JG, Libby P. Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol. 1987;139:1902-1910.
76. Warner SJ, Auger KR, Libby P. Human interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cells. J Exp Med. 1987;165:1316-1331.
77. Ridker PM, Everett BM, Thuren T, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119-1131. doi: 10.1056/NEJMoa1707914.
78. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ; CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: A secondary analysis from the CANTOS randomised controlled trial [published online ahead of print November 13, 2017]. Lancet. doi: http://dx.doi. org/10.1016/S0140-6736(17)32814-3. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32814-3/fulltext.
79. Baylis RA, Gomez D, Mallat Z, Pasterkamp G, Owens GK. The CANTOS Trial: one important step for clinical cardiology but a giant leap for vascular biology. Arterioscler Thromb Vasc Biol. 2017;37:e174-e177. doi: 10.1161/ATVBAHA.117.310097.
80. Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118:145-156. doi: 10.1161/CIRCRESAHA.115.306656.
81. Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: A test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013;166:199.e15-207.e15. doi: 10.1016/j.ahj.2013.03.018.
82. Tardif JC, L'Allier PL. Colchicine Cardiovascular Outcomes Trial (COLCOT). https://www.clinicaltrials.gov/ct2/show/NCT02551094?term =colcot&rank=1. Accessed January 2, 2018.
83. Cole CB, Russler-Germain DA, Ketkar S, et al. Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies. J Clin Invest. 2017;127:3657-3674. doi: 10.1172/JCI93041.
84. Leoni C, Montagner S, Rinaldi A, Bertoni F, Polletti S, Balestrieri C, Monticelli S. Dnmt3a restrains mast cell inflammatory responses. Proc Natl Acad Sci USA. 2017;114:E1490-E1499. doi: 10.1073/pnas.1616420114.
85. Gamper CJ, Agoston AT, Nelson WG, Powell JD. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol. 2009;183:2267-2276. doi: 10.4049/jimmunol.0802960.
86. Pham D, Yu Q, Walline CC, Muthukrishnan R, Blum JS, Kaplan MH. Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation. J Immunol. 2013;191:902-911. doi: 10.4049/jimmunol.1203229.
87. Yu Q, Zhou B, Zhang Y, Nguyen ET, Du J, Glosson NL, Kaplan MH. DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation. Proc Natl Acad Sci USA. 2012;109:541-546. doi: 10.1073/pnas.1103803109.
88. Rodríguez-Ubreva J, Català-Moll F, Obermajer N, Álvarez-Errico D, Ramirez RN, Company C, Vento-Tormo R, Moreno-Bueno G, Edwards RP, Mortazavi A, Kalinski P, Ballestar E. Prostaglandin E2 leads to the acquisition of DNMT3A-dependent tolerogenic functions in human myeloid-derived suppressor cells. Cell Rep. 2017;21:154-167. doi: 10.1016/j. celrep.2017.09.018.
89. Li X, Zhang Q, Ding Y, Liu Y, Zhao D, Zhao K, Shen Q, Liu X, Zhu X, Li N, Cheng Z, Fan G, Wang Q, Cao X. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat Immunol. 2016;17:806-815. doi: 10.1038/ni.3464.
90. Cardilo-Reis L, Gruber S, Schreier SM, Drechsler M, Papac-Milicevic N, Weber C, Wagner O, Stangl H, Soehnlein O, Binder CJ. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med. 2012;4:1072-1086. doi: 10.1002/emmm.201201374.
91. Goossens P, Gijbels MJ, Zernecke A, Eijgelaar W, Vergouwe MN, van der Made I, Vanderlocht J, Beckers L, Buurman WA, Daemen MJ, Kalinke U, Weber C, Lutgens E, de Winther MP. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Cell Metab. 2010;12:142-153. doi: 10.1016/j.cmet.2010.06.008.
92. Campbell PJ, Scott LM, Buck G, et al; United Kingdom Myeloproliferative Disorders Study Group; Medical Research Council Adult Leukaemia Working Party; Australasian Leukaemia and Lymphoma Group. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: A prospective study. Lancet. 2005;366:1945-1953. doi: 10.1016/S0140-6736(05)67785-9.
93. Cheung B, Radia D, Pantelidis P, Yadegarfar G, Harrison C. The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia. Br J Haematol. 2006;132:244-245. doi: 10.1111/j.1365-2141.2005.05858.x.
94. Finazzi G, Rambaldi A, Guerini V, Carobbo A, Barbui T. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2 V617F mutation status. Haematologica. 2007;92:135-136.
95. Hsiao HH, Yang MY, Liu YC, Lee CP, Yang WC, Liu TC, Chang CS, Lin SF. The association of JAK2V617F mutation and leukocytosis with thrombotic events in essential thrombocythemia. Exp Hematol. 2007;35:1704-1707. doi: 10.1016/j.exphem.2007.08.011.
96. Kittur J, Knudson RA, Lasho TL, Finke CM, Gangat N, Wolanskyj AP, Li CY, Wu W, Ketterling RP, Pardanani A, Tefferi A. Clinical correlates of JAK2V617F allele burden in essential thrombocythemia. Cancer. 2007;109:2279-2284. doi: 10.1002/cncr.22663.
97. Vannucchi AM, Antonioli E, Guglielmelli P, Longo G, Pancrazzi A, Ponziani V, Bogani C, Ferrini PR, Rambaldi A, Guerini V, Bosi A, Barbui T; MPD Research Consortium. Prospective identification of highrisk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia. 2007;21:1952-1959. doi: 10.1038/sj.leu.2404854.
98. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110:840-846. doi: 10.1182/blood-2006-12-064287.
99. Dahabreh IJ, Zoi K, Giannouli S, Zoi C, Loukopoulos D, Voulgarelis M. Is JAK2 V617F mutation more than a diagnostic index? A metaanalysis of clinical outcomes in essential thrombocythemia. Leuk Res. 2009;33:67-73. doi: 10.1016/j.leukres.2008.06.006.
100. Xavier SG, Gadelha T, Rezende SM, Zalcberg IR, Spector N. JAK2V617F mutation in patients with thrombosis: To screen or not to screen? Int J Lab Hematol. 2011;33:117-124. doi: 10.1111/j.1751-553X.2010.01275.x.
101. Jaiswal S, Natarajan P, Ebert BL. Clonal hematopoiesis and atherosclerosis. N Engl J Med. 2017;377:1401-1402. doi: 10.1056/NEJMc1710381.
102. Lundberg P, Takizawa H, Kubovcakova L, Guo G, Hao-Shen H, Dirnhofer S, Orkin SH, Manz MG, Skoda RC. Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F. J Exp Med. 2014;211:2213-2230. doi: 10.1084/jem.20131371.
103. Okugawa S, Ota Y, Kitazawa T, Nakayama K, Yanagimoto S, Tsukada K, Kawada M, Kimura S. Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages. Am J Physiol Cell Physiol. 2003;285:C399-C408. doi: 10.1152/ajpcell.00026.2003.
104. Oku S, Takenaka K, Kuriyama T, Shide K, Kumano T, Kikushige Y, Urata S, Yamauchi T, Iwamoto C, Shimoda HK, Miyamoto T, Nagafuji K, Kishimoto J, Shimoda K, Akashi K. JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation. Br J Haematol. 2010;150:334-344. doi: 10.1111/j.1365-2141.2010.08249.x.
105. Desai HR, Sivasubramaniyam T, Revelo XS, et al. Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation. Sci Rep. 2017;7:7653. doi: 10.1038/s41598-017-07923-0.
106. Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22:180-193. doi: 10.1016/j.ccr.2012.06.032.
107. Balasubramani A, Larjo A, Bassein JA, Chang X, Hastie RB, Togher SM, Lähdesmäki H, Rao A. Cancer-Associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex. Nat Commun. 2015;6:7307. doi: 10.1038/ncomms8307.
108. Yang H, Kurtenbach S, Guo Y, et al. Gain-of-function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies [published online ahead of print November 7, 2017]. Blood. doi: 10.1182/blood-2017-06-789669. http://www.bloodjournal.org/content/early/2017/11/07/blood-2017-06-789669.long.
109. Sano S, Oshima K, Wang Y, MacLauchlan S, Katanasaka Y, Sano M, Zuriaga MA, Yoshiyama M, Goukassian D, Cooper MA, Fuster JJ, Walsh K. Tet2-mediated clonal hematopoiesis accelerates experimental heart failure through an IL-1β/NLRP3 inflammasome mechanism. J Am Coll Cardiol. 2018. In press.
110. Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis harbouring AML-Associated mutations is ubiquitous in healthy adults. Nat Commun. 2016;7:12484. doi: 10.1038/ncomms12484.
111. Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518:552-555. doi: 10.1038/nature13968.
112. Hinds DA, Barnholt KE, Mesa RA, Kiefer AK, Do CB, Eriksson N, Mountain JL, Francke U, Tung JY, Nguyen HM, Zhang H, Gojenola L, Zehnder JL, Gotlib J. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood. 2016;128:1121-1128. doi: 10.1182/blood-2015-06-652941.
113. Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, Hyman DM, Solit DB, Robson ME, Baselga J, Arcila ME, Ladanyi M, Tallman MS, Levine RL, Berger MF. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell. 2017;21:374.e4-382.e4. doi: 10.1016/j.stem.2017.07.010.
114. Behfar A, Crespo-Diaz R, Terzic A, Gersh BJ. Cell therapy for cardiac repair-lessons from clinical trials. Nat Rev Cardiol. 2014;11:232-246. doi: 10.1038/nrcardio.2014.9.
115. Turner L, Knoepfler P. Selling stem cells in the USA: Assessing the directto-consumer industry. Cell Stem Cell. 2016;19:154-157. doi: 10.1016/j. stem.2016.06.007.
116. Afzal MR, Samanta A, Shah ZI, Jeevanantham V, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy for ischemic heart disease: evidence and insights from randomized controlled trials. Circ Res. 2015;117:558-575. doi: 10.1161/CIRCRESAHA.114.304792.
117. Klein AM, Simons BD. Universal patterns of stem cell fate in cycling adult tissues. Development. 2011;138:3103-3111. doi: 10.1242/dev.060103.