Clonal hematopoiesis, aging, and cardiovascular diseases
2019; Elsevier BV; Volume: 83; Linguagem: Inglês
10.1016/j.exphem.2019.12.006
ISSN1873-2399
AutoresEvangelia Pardali, Stefanie Dimmeler, Andreas M. Zeiher, Michael A. Rieger,
Tópico(s)Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Resumo•Clonal hematopoiesis (CH) is associated with atherosclerosis, heart failure, and stroke.•Common risk factors prompt CH, cancer, and cardiovascular diseases (CVD).•Inflammation promotes CVD and affects tissue regeneration.•The outcome of heart failure and aortic valve stenosis patients with DNMT3A/TET2-CH mutations is poor.•A vicious circuit is induced by CH-mutated myeloid cells on CVDs and hematopoiesis. Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Many studies have provided evidence that both genetic and environmental factors induce atherosclerosis, leading thus to cardiovascular complications. Atherosclerosis is an inflammatory disease, and aging is strongly associated with the development of atherosclerosis. Recent experimental evidence suggests that clonal hematopoiesis (CH) is an emerging cardiovascular risk factor that contributes to the development of atherosclerosis and cardiac dysfunction and exacerbates cardiovascular diseases. CH is caused by somatic mutations in recurrent genes in hematopoietic stem cells, leading to the clonal expansion of mutated blood cell clones. Many of the mutated genes are known in the context of myeloid neoplasms. However, only some individuals carrying CH mutations develop hematologic abnormalities. CH is clearly age dependent and is not rare: at least 10%–20% of people >70 years old carry CH. The newly discovered association between myeloid leukemia-driver mutations and the progression of CVDs has raised medical interest. In this review, we summarize the current view on the contribution of CH in different cardiovascular diseases, CVD risk assessment, patient stratification, and the development of novel therapeutic strategies. Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Many studies have provided evidence that both genetic and environmental factors induce atherosclerosis, leading thus to cardiovascular complications. Atherosclerosis is an inflammatory disease, and aging is strongly associated with the development of atherosclerosis. Recent experimental evidence suggests that clonal hematopoiesis (CH) is an emerging cardiovascular risk factor that contributes to the development of atherosclerosis and cardiac dysfunction and exacerbates cardiovascular diseases. CH is caused by somatic mutations in recurrent genes in hematopoietic stem cells, leading to the clonal expansion of mutated blood cell clones. Many of the mutated genes are known in the context of myeloid neoplasms. However, only some individuals carrying CH mutations develop hematologic abnormalities. CH is clearly age dependent and is not rare: at least 10%–20% of people >70 years old carry CH. The newly discovered association between myeloid leukemia-driver mutations and the progression of CVDs has raised medical interest. In this review, we summarize the current view on the contribution of CH in different cardiovascular diseases, CVD risk assessment, patient stratification, and the development of novel therapeutic strategies. Despite advances in the medical and interventional clinical management of patients, cardiovascular diseases (CVDs) remain the leading cause of death worldwide. It is well appreciated that atherosclerosis represents the underlying cause of most CVDs [1Libby P. History of discovery: inflammation in atherosclerosis.Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051Crossref PubMed Scopus (1041) Google Scholar]. Atherosclerosis is a chronic inflammatory disease that leads to the formation of atheromatous lesions in the vessel associated with increased recruitment, adhesion, and proliferation of different leukocyte subsets to the endothelium [1Libby P. History of discovery: inflammation in atherosclerosis.Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051Crossref PubMed Scopus (1041) Google Scholar]. Several cardiovascular risk factors (CRFs) have been found to enhance the risk of CVD (Figure 1), including hypercholesterolemia (HC), diabetes mellitus (DM), hypertension, metabolic syndrome, obesity, and smoking [2Pardali E Waltenberger J. Monocyte function and trafficking in cardiovascular disease.Thromb Haemost. 2012; 108: 804-811Crossref PubMed Scopus (14) Google Scholar]. Inflammation plays a crucial role in the development of CVDs and several studies have reported that CRFs enhance production of myeloid cells and multipotent hematopoietic progenitors in the bone marrow and in this way may promote atherosclerosis and disease development [3Dragoljevic D Westerterp M Veiga CB Nagareddy P Murphy AJ Disordered haematopoiesis and cardiovascular disease: a focus on myelopoiesis.Clin Sci (Lond). 2018; 132: 1889-1899Crossref PubMed Scopus (0) Google Scholar]. Increasing evidence suggests that conventional CRFs are not fully predictive of the development of CVDs and, more importantly, that the incidence of CVDs increases with age [4North BJ Sinclair DA. The intersection between aging and cardiovascular disease.Circ Res. 2012; 110: 1097-1108Crossref PubMed Scopus (302) Google Scholar,5Fajemiroye JO da Cunha LC Saavedra-Rodríguez R et al.Aging-induced biological changes and cardiovascular diseases.BioMed Res Int. 2018; 20187156435Crossref PubMed Scopus (0) Google Scholar]. Although the effect of aging on the development of atherosclerosis has been considered to be caused by cumulative exposure to classic CRFs, the exact molecular mechanisms of age predisposition to CVDs are not completely understood. Several studies have linked cardiovascular aging to genomic instability, telomere attrition, and accumulating irreversible epigenetic alterations, including DNA methylation, histone posttranslational modifications, and dynamic nucleosome occupancy [6Zhang W Song M Qu J Liu GH Epigenetic modifications in cardiovascular aging and diseases.Circ Res. 2018; 123: 773-786Crossref PubMed Scopus (21) Google Scholar, 7Zarzour A Kim HW Weintraub NL Epigenetic regulation of vascular diseases.Arterioscler Thromb Vasc Biol. 2019; 39: 984-990Crossref PubMed Scopus (0) Google Scholar, 8Gallagher KA Joshi A Carson WF et al.Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes.Diabetes. 2015; 64: 1420-1430Crossref PubMed Google Scholar]. Recent elegant studies have provided evidence that clonal hematopoiesis (CH) is a novel causal CRF for CVDs in elderly individuals, as previously reviewed [9Sano S Wang Y Walsh K Clonal hematopoiesis and its impact on cardiovascular disease.Circ J. 2018; 83: 2-11Crossref PubMed Scopus (9) Google Scholar,10Libby P Sidlow R Lin AE et al.Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week.J Am Coll Cardiol. 2019; 74: 567-577Crossref PubMed Scopus (9) Google Scholar]. CH was initially described in elderly people who develop hematologic malignancies. CH originates from somatic mutations in hematopoietic stem cells (HSCs) in genes implicated in myeloid neoplasms and results in expansion of mutated blood cell clones. Clonal hematopoiesis of indeterminate potential (CHIP) is technically defined by the presence of somatic variants with a variant allele frequency (VAF) (i.e., variant prevalence among all blood cells) of at least 2%, but without the presence of hematologic malignancies or other hematologic abnormalities [11Steensma DP Bejar R Jaiswal S et al.Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.Blood. 2015; 126: 9-16Crossref PubMed Scopus (566) Google Scholar]. Genetic and epidemiology studies in humans revealed that CHIP correlated with increased mortality in individuals with CVDs. Preclinical animal models provided mechanistic evidence for the role of CHIP in the progression and development of CVD. In this review, we summarize the role of inflammation and inflammatory blood cell types in the development of atherosclerosis and CVDs. We also discuss the potential mechanisms by which CH contributes to increased cardiovascular risk in aging individuals and how increased inflammation, induced by cardiovascular risk factors, further promotes the clonal dominance of mutated HSC clones, leading to a feedback loop between CH and CVDs. Finally, we raise potential implications of these findings in CVD risk assessment, patient stratification, and the development of novel therapeutic strategies. Atherosclerosis is a chronic inflammatory disease of the vasculature. It is well appreciated that monocyte-derived macrophages play a crucial role in the progression of atherosclerosis, plaque development, and the incidence of CVD [1Libby P. History of discovery: inflammation in atherosclerosis.Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051Crossref PubMed Scopus (1041) Google Scholar,2Pardali E Waltenberger J. Monocyte function and trafficking in cardiovascular disease.Thromb Haemost. 2012; 108: 804-811Crossref PubMed Scopus (14) Google Scholar]. Pathological stimuli such as hyperlipidemia and hypertension increase monocyte adhesion on the endothelium and their infiltration into the vessel wall during atherogenesis [1Libby P. History of discovery: inflammation in atherosclerosis.Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051Crossref PubMed Scopus (1041) Google Scholar,2Pardali E Waltenberger J. Monocyte function and trafficking in cardiovascular disease.Thromb Haemost. 2012; 108: 804-811Crossref PubMed Scopus (14) Google Scholar]. After entering the vessel wall, monocytes start to proliferate and differentiate into macrophages, which endocytose lipids and develop into foam cells, which contribute to plaque development [1Libby P. History of discovery: inflammation in atherosclerosis.Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051Crossref PubMed Scopus (1041) Google Scholar,2Pardali E Waltenberger J. Monocyte function and trafficking in cardiovascular disease.Thromb Haemost. 2012; 108: 804-811Crossref PubMed Scopus (14) Google Scholar]. It has been reported that increased numbers of circulating monocytes (monocytosis) correlate with plaque formation and the development of carotid artery disease (CAD) [1Libby P. History of discovery: inflammation in atherosclerosis.Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051Crossref PubMed Scopus (1041) Google Scholar,12Olivares R Ducimetière P Claude JR Monocyte count: a risk factor for coronary heart disease?.Am J Epidemiol. 1993; 137: 49-53Crossref PubMed Google Scholar,13Johnsen SH et al.Monocyte count is a predictor of novel plaque formation: a 7-year follow-up study of 2610 persons without carotid plaque at baseline the Tromsø Study.Stroke. 2005; 36: 715-719Crossref PubMed Scopus (101) Google Scholar]. Experimental evidence has established a causal relationship between monocytosis and the development of atherosclerosis in preclinical models [1Libby P. History of discovery: inflammation in atherosclerosis.Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051Crossref PubMed Scopus (1041) Google Scholar,2Pardali E Waltenberger J. Monocyte function and trafficking in cardiovascular disease.Thromb Haemost. 2012; 108: 804-811Crossref PubMed Scopus (14) Google Scholar]. Monocyte depletion or inhibition of monocyte recruitment results in reduced atherogenesis and plaque formation in experimental models of atherosclerosis [14Ylitalo R Oksala O Ylä-Herttuala S Ylitalo P Effects of clodronate (dichloromethylene bisphosphonate) on the development of experimental atherosclerosis in rabbits.J Lab Clin Med. 1994; 123: 769-776PubMed Google Scholar, 15Stoneman V et al.Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques.Circ Res. 2007; 100: 884-893Crossref PubMed Scopus (191) Google Scholar, 16Rajavashisth T Qiao JH Tripathi S et al.Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor-deficient mice.J Clin Invest. 1998; 101: 2702-2710Crossref PubMed Google Scholar, 17Bannon P Wood S Restivo T Campbell L Hardman MJ Mace KA Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice.Dis Model Mech. 2013; 6: 1434-1447Crossref PubMed Scopus (43) Google Scholar, 18Potteaux S Gautier EL Hutchison SB et al.Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe–/– mice during disease regression.J Clin Invest. 2011; 121: 2025-2036Crossref PubMed Scopus (223) Google Scholar]. Several CRFs have been found to increase the risk of CVDs by inducing myelopoiesis and hematopoiesis (Figure 1). Hypercholesterolemia, diabetes, and obesity increase the number of circulating monocytes, resulting thus in acceleration of atherosclerosis [19Nagareddy PR Murphy AJ Stirzaker RA et al.Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.Cell Metab. 2013; 17: 695-708Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 20Nagareddy PR Kraakman M Masters SL et al.Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity.Cell Metab. 2014; 19: 821-835Abstract Full Text Full Text PDF PubMed Google Scholar, 21Swirski FK Libby P Aikawa E et al.Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.J Clin Invest. 2007; 117: 195-205Crossref PubMed Scopus (800) Google Scholar]. 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Similarly, other studies have found that diabetes and hyperglycemia influence HSC function, differentiation, and mobilization and in this way further contribute to the development of CVDs [27Ferraro F Lymperi S Méndez-Ferrer S et al.Diabetes impairs hematopoietic stem cell mobilization through alteration of niche function.Sci Transl Med. 2011; 3: 104ra101Crossref PubMed Scopus (0) Google Scholar, 28Hazra S Jarajapu YPR Stepps V et al.Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model.Diabetologia. 2013; 56: 644-653Crossref PubMed Scopus (46) Google Scholar, 29Orlandi A Chavakis E Seeger F Tjwa M Zeiher AM Dimmeler S Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice.Basic Res Cardiol. 2010; 105: 703-712Crossref PubMed Scopus (70) Google Scholar]. Diabetes results in reduced numbers of HSCs and interferes with their repopulation capacity in a competitive engraftment experiment and their cytokine expression patterns [29Orlandi A Chavakis E Seeger F Tjwa M Zeiher AM Dimmeler S Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice.Basic Res Cardiol. 2010; 105: 703-712Crossref PubMed Scopus (70) Google Scholar]. Furthermore, diabetes leads to increased expression of plasma levels of the alarmins S100A8 and S100A9 secreted by neutrophils, resulting in increased proliferation of granulocyte–monocyte progenitors (GMPs) and enhanced myelopoiesis [19Nagareddy PR Murphy AJ Stirzaker RA et al.Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.Cell Metab. 2013; 17: 695-708Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar,20Nagareddy PR Kraakman M Masters SL et al.Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity.Cell Metab. 2014; 19: 821-835Abstract Full Text Full Text PDF PubMed Google Scholar]. Clearly, aging poses the largest risk for the development of CVDs; this is due not only to the accumulative effect of the CRFs and the increased inflammatory responses but also to the accumulation of epigenetic alterations and genetic mutations. It was recently reported that CHIP contributes to the development of cardiovascular diseases in elderly individuals [30Jaiswal S Natarajan P Ebert BL Clonal hematopoiesis and atherosclerosis.N Engl J Med. 2017; 377: 1401-1402Crossref PubMed Scopus (326) Google Scholar, 31Jaiswal S Fontanillas P Flannick J et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1291) Google Scholar, 32Jaiswal S Natarajan P Silver AJ et al.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med. 2017; 377: 111-121Crossref PubMed Scopus (395) Google Scholar, 33Genovese G Kahler AK Handsaker RE et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1070) Google Scholar]. Before discussing the role of CHIP in the development of CVD, it is important to review the basis of CH. Hematological malignancies ensue from the clonal expansion of transformed blood cells, and are generally diseases of the elderly, as the median age for most of these diseases is between 60 and 70 years. Although, in certain cases, they can be associated with inherited genetic mutations, hematologic malignancies usually originate from recurrent somatic mutations in driver genes [34Welch JS Ley TJ Link DC et al.The origin and evolution of mutations in acute myeloid leukemia.Cell. 2012; 150: 264-278Abstract Full Text Full Text PDF PubMed Scopus (880) Google Scholar,35Bowman RL Busque L Levine RL Clonal hematopoiesis and evolution to hematopoietic malignancies.Cell Stem Cell. 2018; 22: 157-170Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. Interestingly, although most of the somatic mutations have no effect, certain mutations result in increased proliferation or, alternatively, reduced cell death and enhanced self-renewal and, as a result, confer a specific clonal expansion advantage to the HSCs carrying these mutations [36Beerman I Bhattacharya D Zandi S et al.Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion.Proc Natl Acad Sci USA. 2010; 107: 5465-5470Crossref PubMed Scopus (329) Google Scholar]; this may lead to hematologic malignancies. Clonality was also found to be a major characteristic of the aging hematopoietic system. Studies in women over the age of 65, with no hematologic malignancies, suggested that there is a skewed pattern of X-chromosome inactivation in peripheral blood cells, particularly within the myeloid compartment, which is age related [37Busque L Mio R Mattioli J et al.Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age.Blood. 1996; 88: 59-65Crossref PubMed Google Scholar, 38Fey MF Liechti-Gallati S von Rohr A et al.Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe.Blood. 1994; 83: 931-938Crossref PubMed Google Scholar, 39Gale 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: 512-519Crossref PubMed Scopus (182) Google Scholar]. Subsequently, Busque and colleagues demonstrated by exome sequencing the presence of somatic, recurrent TET2 mutations in normal elderly individuals with clonal hematopoiesis but without hematological malignancies [40Busque L Patel JP Figueroa M et al.Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis.Nat Genet. 2012; 44: 1179-1181Crossref PubMed Scopus (411) Google Scholar]. TET2 mutations were previously reported to be associated with myeloid cancers [41Delhommeau F Dupont S Della Valle V et al.Mutation in TET2 in myeloid cancers.N Engl J Med. 2009; 360: 2289-2301Crossref PubMed Scopus (1170) Google Scholar]. Subsequent studies using whole-exome sequencing as well as gene-targeted sequencing assisted the detection of several somatic mutations with low VAF [31Jaiswal S Fontanillas P Flannick J et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1291) Google Scholar, 32Jaiswal S Natarajan P Silver AJ et al.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med. 2017; 377: 111-121Crossref PubMed Scopus (395) Google Scholar, 33Genovese G Kahler AK Handsaker RE et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1070) Google Scholar]. These studies provided evidence that the majority of the age-associated recurrent mutations were in genes such as DNMT3A, TET2, JAK2, TP53, ASXL1, SF3B1, PPM1D, and BCORL1, known to be associated with acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), or myelodysplastic syndrome (MDS) [42Xie M Lu C Wang J et al.Age-related cancer mutations associated with clonal hematopoietic expansion.Nat Med. 2014; 20: 1472-1478Crossref PubMed Scopus (720) Google Scholar]. Interestingly, other mutations in genes found to play an important role in AML development and progression, such as FLT3, IDH1, IDH2, and NPM1, were not so common in CH [30Jaiswal S Natarajan P Ebert BL Clonal hematopoiesis and atherosclerosis.N Engl J Med. 2017; 377: 1401-1402Crossref PubMed Scopus (326) Google Scholar, 31Jaiswal S Fontanillas P Flannick J et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1291) Google Scholar, 32Jaiswal S Natarajan P Silver AJ et al.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med. 2017; 377: 111-121Crossref PubMed Scopus (395) Google Scholar,42Xie M Lu C Wang J et al.Age-related cancer mutations associated with clonal hematopoietic expansion.Nat Med. 2014; 20: 1472-1478Crossref PubMed Scopus (720) Google Scholar, 43Coombs CC Zehir A Devlin SM et al.Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.Cell Stem Cell. 2017; 21 (e4): 374-382Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 44Papaemmanuil E Gerstung M Bullinger L et al.Genomic classification and prognosis in acute myeloid leukemia.N Engl J Med. 2016; 374: 2209-2221Crossref PubMed Scopus (995) Google Scholar]. All identified mutations increased with age. Subsequent complementary studies of large cohorts of patients utilizing sensitive error-corrected, targeted deep sequencing [45Abelson S Collord G Ng SWK et al.Prediction of acute myeloid leukaemia risk in healthy individuals.Nature. 2018; 559: 400-404Crossref PubMed Scopus (118) Google Scholar,46Young AL Challen GA Birmann BM Druley TE Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.Nat Commun. 2016; 7: 12484Crossref PubMed Google Scholar] further supported these results, indicating that recurrent mutations in genes associated with leukemia are increased in aged individuals and correlated with clonal hematopoiesis [30Jaiswal S Natarajan P Ebert BL Clonal hematopoiesis and atherosclerosis.N Engl J Med. 2017; 377: 1401-1402Crossref PubMed Scopus (326) Google Scholar, 31Jaiswal S Fontanillas P Flannick J et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1291) Google Scholar, 32Jaiswal S Natarajan P Silver AJ et al.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med. 2017; 377: 111-121Crossref PubMed Scopus (395) Google Scholar, 33Genovese G Kahler AK Handsaker RE et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1070) Google Scholar,46Young AL Challen GA Birmann BM Druley TE Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.Nat Commun. 2016; 7: 12484Crossref PubMed Google Scholar, 47Shlush LI Zandi S Mitchell A et al.Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.Nature. 2014; 506: 328-333Crossref PubMed Scopus (744) Google Scholar, 48McKerrell T Park N Moreno T et al.Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis.Cell Rep. 2015; 10: 1239-1245Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar], but without leading to hematological malignancies. This type of CH was technically defined as CHIP and is characterized by the presence of recurrent mutations with a VAF of at least 2% in aged individuals in the absence of hematologic cancer or other clonal disease [11Steensma DP Bejar R Jaiswal S et al.Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.Blood. 2015; 126: 9-16Crossref PubMed Scopus (566) Google Scholar]. Although the frequency of CHIP is less than 1% in individuals younger than 40 years, its prevalence increases to 15%–20% in people older than 70 years [31Jaiswal S Fontanillas P Flannick J et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1291) Google Scholar,33Genovese G Kahler AK Handsaker RE et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1070) Google Scholar,42Xie M Lu C Wang J et al.Age-related cancer mutations associated with clonal hematopoietic expansion.Nat Med. 2014; 20: 1472-1478Crossref PubMed Scopus (720) Google Scholar,43Coombs CC Zehir A Devlin SM et al.Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.Cell Stem Cell. 2017; 21 (e4): 374-382Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. However, the prevalence of CH is highly dependent on the sensitivity of the detection method used. Although the initial studies used whole-exome sequencing, which is relatively insensitive to smaller clones, recent studies using more sensitive, error-corrected, deep sequencing approaches have found a much higher prevalence of CH with low VAF, even at younger age. The biological and medical importance of the smaller clones still remains unclear [45Abelson S Collord G Ng SWK et al.Prediction of acute myeloid leukaemia risk in healthy individuals.Nature. 2018; 559: 400-404Crossref PubMed Scopus (118) Google Scholar,49Acuna-Hidalgo R Sengul H Steehouwer M et al.Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis-associated mutations throughout adult life.Am J Hum Genet. 2017; 101: 50-64Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. Although CH was initially associated with hematologic malignancies, it became evident that CH led to decreased patient survival, which could not be explained by the increase in hematological cancer [30Jaiswal S Natarajan P Ebert BL Clonal hematopoiesis and atherosclerosis.N Engl J Med. 2017; 377: 1401-1402Crossref PubMed Scopus (326) Google Scholar, 31Jaiswal S Fontanillas P Flannick J et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1291) Google Scholar, 32Jaiswal S Natarajan P Silver AJ et al.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med. 2017; 377: 111-121Crossref PubMed Scopus (395) Google Scholar, 33Genovese G Kahler AK Handsaker RE et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1070) Google Scholar,43Coombs CC Zehir A Devlin SM et al.Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and impacts clinical outcome.Cell Stem Cell. 2017; 21 (e4): 374-382Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] Different studies using next-generation sequencing analysis in large cohorts revealed that CHIP-driver mutations in leukemia-related genes DNMT3A, TET2, ASXL1, and JAK2 were associated with an increased risk of incidence of coronary heart disease (CHD) or stroke and increased mortality [30Jaiswal S Natarajan P Ebert BL Clonal hematopoiesis and atherosclerosis.N Engl J Med. 2017; 377: 1401-1402Crossref PubMed Scopus (326) Google Scholar, 31Jaiswal S Fontanillas P Flannick J et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1291) Google Scholar, 32Jaiswal S Natarajan P Silver AJ et al.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med. 2017; 377: 111-121Crossref PubMed Scopus (395) Google Scholar]. Importantly it was reported that the
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