Clonal hematopoiesis and inflammation: Partners in leukemogenesis and comorbidity
2020; Elsevier BV; Volume: 83; Linguagem: Inglês
10.1016/j.exphem.2020.01.011
ISSN1873-2399
AutoresElina K. Cook, Michael Luo, Michael J. Rauh,
Tópico(s)Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Resumo•CH expansion and inflammation may support each other in a self-perpetuating cycle.•High levels of IL-6 and TNF-α promote the expansion of Tet2-deficient murine HSCs.•CH-mutant macrophages, T lymphocytes, and granulocytes may contribute to the inflammatory milieu and related comorbidities.•Proposed interventions for CH focus on controlling excessive inflammation. Clonal hematopoiesis (CH) of indeterminate potential (CHIP), defined as the presence of a somatic mutation in the peripheral blood at a variant allele frequency (VAF) ≥2%, affects at least 10% of individuals older than 65, but low-VAF clones can be detected in 95% of individuals older than 50. CHIP associates with a wide range of comorbidities from atherosclerosis to pulmonary disease. A growing body of evidence, primarily from studies involving Tet2-knockout and stem cell transplant models of CH, suggest that dysregulated inflammation contributes to clonal expansion and associated comorbidities. Mutant leukocytes from animal models contribute to an inflammatory milieu that may confer a selective advantage to the clone, thus perpetuating a cycle of inflammation and expansion. Although it is unclear whether inflammation or expansion sets this cycle in motion, some evidence suggests that inflammation from infections or pre-existing comorbidities initiates this cycle. The pro-inflammatory phenotypes of macrophages from mutant clones and their contributions to disease are well characterized in murine models, but have not yet been confirmed in humans. Furthermore, the roles of other cell types that can carry mutations of CHIP are not fully understood. We propose a rationale for further investigation of neutrophils, other granulocytes and T, B, and NK cells as they may play a role in CHIP-associated comorbidities. As the understanding of CH has advanced, potential interventions, especially those targeting aberrant inflammation, have been proposed. We are hopeful that as studies continue to unravel the complex links between CHIP, inflammation, and leukocyte dysfunction, CHIP-related comorbidities may be more effectively managed. Clonal hematopoiesis (CH) of indeterminate potential (CHIP), defined as the presence of a somatic mutation in the peripheral blood at a variant allele frequency (VAF) ≥2%, affects at least 10% of individuals older than 65, but low-VAF clones can be detected in 95% of individuals older than 50. CHIP associates with a wide range of comorbidities from atherosclerosis to pulmonary disease. A growing body of evidence, primarily from studies involving Tet2-knockout and stem cell transplant models of CH, suggest that dysregulated inflammation contributes to clonal expansion and associated comorbidities. Mutant leukocytes from animal models contribute to an inflammatory milieu that may confer a selective advantage to the clone, thus perpetuating a cycle of inflammation and expansion. Although it is unclear whether inflammation or expansion sets this cycle in motion, some evidence suggests that inflammation from infections or pre-existing comorbidities initiates this cycle. The pro-inflammatory phenotypes of macrophages from mutant clones and their contributions to disease are well characterized in murine models, but have not yet been confirmed in humans. Furthermore, the roles of other cell types that can carry mutations of CHIP are not fully understood. We propose a rationale for further investigation of neutrophils, other granulocytes and T, B, and NK cells as they may play a role in CHIP-associated comorbidities. As the understanding of CH has advanced, potential interventions, especially those targeting aberrant inflammation, have been proposed. We are hopeful that as studies continue to unravel the complex links between CHIP, inflammation, and leukocyte dysfunction, CHIP-related comorbidities may be more effectively managed. A limited number of hematopoietic stem cells (HSCs) lie at the top of the hematopoietic hierarchy. Any peculiarities that arise in advantaged HSCs are carried into the peripheral expanse. In the last 5 years, small, mutated HSC clones emerged as risk factors for the developed world's most prevalent diseases—cardiovascular disease and cancer. Enter, clonal hematopoiesis (CH). Normal, polyclonal hematopoiesis can become skewed toward a particular HSC or clone. CH arises when an HSC acquires a somatic mutation that provides a growth or survival advantage and produces a disproportionately large fraction of mature peripheral leukocytes, collectively called a clone [1Steensma 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 (805) Google Scholar,2Shlush LI Zandi S Mitchell A et al.Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.Nature. 2014; 506: 328-333Crossref PubMed Scopus (897) Google Scholar]. The clone size matters from both a technical and a biological perspective. Large increases in blood cell skewing for healthy women >60 years of age were reported as early as the late 1990s [3Busque 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]. With the advent of next-generation sequencing (NGS) technologies, a reliable level of detection of the mutant clone among the peripheral leukocytes was deemed to be 2% variant allele frequency (VAF), corresponding to 4% of heterozygous mutation-carrying blood cells and associating with clinically significant outcomes [1Steensma 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 (805) Google Scholar]. This was termed CH of indeterminate potential, or CHIP, and CHIP prevalence unanimously increases with age, with rapid accumulation to >10% of people after age 65 [1Steensma 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 (805) Google Scholar]. In this review, we focus on "CHIP" when describing human studies; we use the term CH to refer to the spectrum of clonal expansion that precedes overt hematological malignancy, which includes CHIP 10,000 participants, CHIP associated with atherosclerotic cardiovascular disease and related complications (myocardial infarction and stroke, albeit with lower burdens of risk than hematologic malignancy) [9Jaiswal 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 (1863) Google Scholar,10Genovese G Kähler AK Handsaker RE et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1504) Google Scholar,21Jaiswal 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 (717) Google Scholar]. Moreover, smaller retrospective studies reveal CHIP as a disease modifier in heart failure and valvulopathy [22Mas-Peiro S et al.Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation.Eur Heart J. 2019; (Epub ahead of print.)https://doi.org/10.1093/eurheartj/ehz591Crossref PubMed Scopus (45) Google Scholar,23Dorsheimer L Assmus B Rasper T et al.Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure.JAMA Cardiol. 2019; 4: 25-33Crossref PubMed Scopus (119) Google Scholar], further suggesting a role for TET2 and DNMT3A mutant monocytes in disease exacerbation. Whereas a causative association between CHIP and atherosclerotic disease and heart failure in humans is further supported by studies in vitro and in mice, other disease correlations with CHIP lack robust causative and mechanistic evidence. For example, pulmonary disease [11Zink F Stacey SN Norddahl GL et al.Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.Blood. 2017; 130: 742-752Crossref PubMed Scopus (271) Google Scholar,24Buscarlet M Provost S Zada YF et al.DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions.Blood. 2017; 130: 753-762Crossref PubMed Scopus (147) Google Scholar,25Cook EK Izukawa T Young S et al.Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis.Blood Adv. 2019; 3: 2482-2486Crossref PubMed Scopus (26) Google Scholar] and diabetes [9Jaiswal 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 (1863) Google Scholar,25Cook EK Izukawa T Young S et al.Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis.Blood Adv. 2019; 3: 2482-2486Crossref PubMed Scopus (26) Google Scholar] are also more likely in people with CHIP, but these correlations may involve antecedent–consequent bias or confounding variables. This limitation also applies to exploratory analyses finding potential links with thyroid dysfunction and gastroesophageal reflux disease [25Cook EK Izukawa T Young S et al.Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis.Blood Adv. 2019; 3: 2482-2486Crossref PubMed Scopus (26) Google Scholar]. Nonetheless, such findings support the investigation of other organ systems for ties with CHIP pathology. Inflammation may explain clonal expansion and disease associations. So far, direct evidence for this in humans is early, minimal, and mainly exploratory, or drawn from related neoplasms (e.g., MDS and myeloproliferative neoplasms [MPNs]). For example, a cross-sectional study of 359 older adults found that people with CHIP have higher serum interleukin (IL)-6 (especially with more than one mutation or TET2 mutations) and tumor necrosis factor (TNF)-α levels than those without CHIP [25Cook EK Izukawa T Young S et al.Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis.Blood Adv. 2019; 3: 2482-2486Crossref PubMed Scopus (26) Google Scholar]. A post hoc serum IL-8 level analysis between people with and without mutant TET2 CHIP clones (and no myocardial infarction) found higher levels among TET2-mutant CHIP. It is worth noting that typical clinical markers of inflammation (C-reactive protein [CRP], white blood cell counts, erythrocyte sedimentation rate [ESR]) are usually not elevated in people with CHIP [9Jaiswal 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 (1863) Google Scholar,25Cook EK Izukawa T Young S et al.Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis.Blood Adv. 2019; 3: 2482-2486Crossref PubMed Scopus (26) Google Scholar]. Mechanisms underlying the disease associations are characterized in mice [26Jaiswal S Libby P Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease.Nat Rev Cardiol. 2019; (Available at:) (Epub ahead of print.)https://doi.org/10.1038/s41569-019-0247-5Crossref PubMed Scopus (45) Google Scholar], and have been macrophage/monocyte focused. We call for broader study of the inflammatory underpinnings of CHIP, in wider cell subsets and contexts, and inclusion of human cells to complement mechanistic studies involving mouse models. Our review summarizes the current understanding of the inflammatory landscape of CH and provides perspectives on future directions. The HSC compartment changes with aging, and is responsive to inflammatory cues (reviewed in Kovtonyuk et al. [27Kovtonyuk LV Fritsch K Feng X Manz MG Takizawa H Inflammaging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment.Front Immunol. 2016; 7: 502Crossref PubMed Scopus (136) Google Scholar]). Aging enriches for myeloid-biased HSCs [28Cho RH Sieburg HB Muller-Sieburg CE A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells.Blood. 2008; 111: 5553-5561Crossref PubMed Scopus (228) Google Scholar], reduces HSC self-renewal capacity, and lowers immune function, rendering people susceptible to disease [27Kovtonyuk LV Fritsch K Feng X Manz MG Takizawa H Inflammaging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment.Front Immunol. 2016; 7: 502Crossref PubMed Scopus (136) Google Scholar]. "Inflammaging," a chronic low-grade inflammation in the form of increased pro-inflammatory cytokines (often IL-6 and TNF) and pro-inflammatory cellular activity with age [29Franceschi C Bonafè M Valensin S et al.Inflamm-aging. An evolutionary perspective on immunosenescence.Ann NY Acad Sci. 2000; 908: 244-254Crossref PubMed Scopus (2544) Google Scholar], may be partly responsible for this gradual shift [27Kovtonyuk LV Fritsch K Feng X Manz MG Takizawa H Inflammaging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment.Front Immunol. 2016; 7: 502Crossref PubMed Scopus (136) Google Scholar]. An inflammatory environment from inflammaging or comorbid background may enable CH emergence with aging (Figure 1). Interestingly, a 359-participant cross-sectional study found that people with DNMT3A mutations are more likely to have multiple comorbidities, compared with those without CHIP [25Cook EK Izukawa T Young S et al.Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis.Blood Adv. 2019; 3: 2482-2486Crossref PubMed Scopus (26) Google Scholar]. Large registries also reveal a causal association between immunological stressors (history of infections or autoimmune disease) and the likelihood of MDS/AML development [30Kristinsson SY Björkholm M Hultcrantz M et al.Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes.J Clin Oncol. 2011; 29: 2897-2903Crossref PubMed Scopus (164) Google Scholar]. Coupled with the finding that high levels of some key cytokines (e.g., IL-6) predict overall survival at MDS diagnosis [31Pardanani A Finke C Lasho TL et al.IPSS-independent prognostic value of plasma CXCL10, IL-7 and IL-6 levels in myelodysplastic syndromes.Leukemia. 2012; 26: 693-699Crossref PubMed Scopus (43) Google Scholar], these suggest that the inflammatory context powerfully influences CHIP emergence and the extent of its pathology. In fact, a surprising 95% of individuals between the ages of 50 and 70 harbor CH mutations (a VAF lower limit of 0.03% is detected by error-corrected targeted sequencing [32Young AL Challen GA Birmann BM Druley TE Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.Nat Commun. 2016; 7: 12484Crossref PubMed Scopus (275) Google Scholar]), leaving a potential role for the inflammatory context in those that progress to CHIP. Experimental support for this hypothesis comes from functional assays of HSCs [33Meisel M Hinterleitner R Pacis A et al.Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host.Nature. 2018; 557: 580-584Crossref PubMed Scopus (117) Google Scholar, 34Cai Z Kotzin JJ Ramdas B et al.Inhibition of inflammatory signaling in Tet2 mutant preleukemic cells mitigates stress-induced abnormalities and clonal hematopoiesis.Cell Stem Cell. 2018; 23: 833-849Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 35Abegunde SO Buckstein R Wells RA Rauh MJ An inflammatory environment containing TNFalpha favors Tet2-mutant clonal hematopoiesis.Exp Hematol. 2018; 59: 60-65Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. The HSC niche may come under inflammatory pressure from a number of triggers. For example, in vitro, Tet2-deficient murine and TET2-mutant human HSCs have a strong proliferative advantage compared with wild-type cells when exposed to high levels of exogenous, pro-inflammatory TNF-α [35Abegunde SO Buckstein R Wells RA Rauh MJ An inflammatory environment containing TNFalpha favors Tet2-mutant clonal hematopoiesis.Exp Hematol. 2018; 59: 60-65Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. Moreover, under inflammatory stress, murine Tet2-deficient HSCs resist apoptosis, rapidly expand, are able to engraft, and produce more pro-inflammatory IL-6 in response [34Cai Z Kotzin JJ Ramdas B et al.Inhibition of inflammatory signaling in Tet2 mutant preleukemic cells mitigates stress-induced abnormalities and clonal hematopoiesis.Cell Stem Cell. 2018; 23: 833-849Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. An additional opportunity for inflammation to promote CH is through infection. Infections exert a strong selective pressure that depletes the wild-type HSC pool [36Kobayashi H Suda T Takubo K How hematopoietic stem/progenitors and their niche sense and respond to infectious stress.Exp Hematol. 2016; 44: 92-100Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,37Matatall KA et al.Chronic infection depletes hematopoietic stem cells through stress-induced terminal differentiation.Cell Rep. 2016; 17: 2584-2595Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar], while HSCs with CH mutations are able to thrive [33Meisel M Hinterleitner R Pacis A et al.Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host.Nature. 2018; 557: 580-584Crossref PubMed Scopus (117) Google Scholar,34Cai Z Kotzin JJ Ramdas B et al.Inhibition of inflammatory signaling in Tet2 mutant preleukemic cells mitigates stress-induced abnormalities and clonal hematopoiesis.Cell Stem Cell. 2018; 23: 833-849Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. In fact, microbial exposure in mice deficient for Tet2 in the hematopoietic system was sufficient and required to elicit myeloid proliferation [33Meisel M Hinterleitner R Pacis A et al.Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host.Nature. 2018; 557: 580-584Crossref PubMed Scopus (117) Google Scholar], while antibiotics reduced the abnormal expansion of Tet2-deficient leukocytes and affected the expression of inflammation-related genes [38Zeng H He H Guo L et al.Antibiotic treatment ameliorates Ten-eleven translocation 2 (TET2) loss-of-function associated hematological malignancies.Cancer Lett. 2019; 467: 1-8Crossref PubMed Scopus (7) Google Scholar]. This, coupled with key features of Tet2-knockout HSCs (higher expression of survival signals, resistance to lipopolysaccharide (LPS)-driven inflammation, and robust repopulation of the bone marrow niche after depletion through severe infections [34Cai Z Kotzin JJ Ramdas B et al.Inhibition of inflammatory signaling in Tet2 mutant preleukemic cells mitigates stress-induced abnormalities and clonal hematopoiesis.Cell Stem Cell. 2018; 23: 833-849Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]), suggests that TET2-mutant cells, and hence some CHIP, may be promoted by infection. It will be interesting to see if other common CHIP-related mutant HSCs (e.g. DNMT3A-mutant clones) respond this way to similar inflammatory cues. In this regard, Challen's group recently found a higher frequency of DNMT3A and PPM1D mutations in ulcerative colitis patients compared with the aggregate incidence across published studies, possibly related to higher levels of serum interferon (IFN)-γ for patients with DNMT3A mutations [39Zhang CRC Nix D Gregory M et al.Inflammatory cytokines promote clonal hematopoiesis with specific mutations in ulcerative colitis patients.Exp Hematol. 2019; 80: 36-41.e3Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. Although this potential phenomenon is only beginning to be studied in humans, it aligns with the current paradigm of a broad role for inflammation in controlling the output of the HSC niche; the human HSC compartment is indeed under heavy influence of inflammatory signals [27Kovtonyuk LV Fritsch K Feng X Manz MG Takizawa H Inflammaging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment.Front Immunol. 2016; 7: 502Crossref PubMed Scopus (136) Google Scholar]. Mutant clonal expansion with an inflammatory driver has also been described in overt hematological cancers [40Fleischman AG Aichberger KJ Luty SB et al.TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms.Blood. 2011; 118: 6392-6398Crossref PubMed Scopus (157) Google Scholar,41Reynaud D Pietras E Barry-Holson K et al.IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development.Cancer Cell. 2011; 20: 661-673Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar]. In particular, inflammation plays a central role in the pathology of MPNs that share many common mutant genes with CHIP, particularly TET2 and JAK2. For example, people with MPNs have higher serum levels of pro-inflammatory TNF-α, and their JAK2V617F-mutated CD34+ bone marrow cells form more colonies in vitro when exposed to TNF-α, compared with the patients' nonmutated CD34+ cells or normal CD34+ cells from controls [40Fleischman AG Aichberger KJ Luty SB et al.TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms.Blood. 2011; 118: 6392-6398Crossref PubMed Scopus (157) Google Scholar]. Similarly, overexpression of IL-6 from mutated granulocytes in a mouse model of chronic myeloid leukemia (another type of MPN, arising from a BCR/ABL1 fusion gene product) promotes myeloid bias in leukemic multipotent progenitors and outcompetition of normal hematopoiesis, thus contributing to the disease [41Reynaud D Pietras E Barry-Holson K et al.IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development.Cancer Cell. 2011; 20: 661-673Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar]. In MDS cells, including those with TET2 mutations, the excessive activation of the NLRP3 inflammasome catalyzes strong pro-inflammatory programming via IL-1β and IL-18, leading to pyroptosis of wild-type HSCs [42Basiorka AA McGraw KL Eksioglu EA et al.The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype.Blood. 2016; 128: 2960-2975Crossref PubMed Scopus (122) Google Scholar]. Thus, a malignant clone may proliferate or survive in a pro-inflammatory setting (e.g., high TNF-α or NLRP3 activation) better than nonmutated HSCs. Pro-inflammatory products of the clone may reinforce and direct its expansion in a para
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