Clonal hematopoiesis (CH) is described as the outsized contribution of expanded clones of hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence of CH increases ...dramatically with age. CH can be caused by somatic mutations in individual genes or by gains and/or losses of larger chromosomal segments. CH is a premalignant state; the somatic mutations detected in CH are the initiating mutations for hematologic malignancies, and CH is a strong predictor of the development of blood cancers. Moreover, CH is associated with nonmalignant disorders and increased overall mortality. The somatic mutations that drive clonal expansion of HSPCs can alter the function of terminally differentiated blood cells, including the release of elevated levels of inflammatory cytokines. These cytokines may then contribute to a broad range of inflammatory disorders that increase in prevalence with age. Specific somatic mutations in the peripheral blood in coordination with blood count parameters can powerfully predict the development of hematologic malignancies and overall mortality in CH. In this review, we summarize the current understanding of CH nosology and origins. We provide an overview of available tools for risk stratification and discuss management strategies for patients with CH presenting to hematology clinics.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell dyscrasia that consistently precedes multiple myeloma (MM) with a 1% risk of progression per year. Recent ...advances have improved understanding of the complex genetic and immunologic factors that permit progression from the aberrant plasma cell clone to MGUS and overt MM. Additional evidence supports bidirectional interaction of MGUS cells with surrounding cells in the bone marrow niche that regulates malignant transformation. However, there are no robust prognostic biomarkers. Herein we review the current body of literature on the biology of MGUS and provide a rationale for the improved identification of high-risk MGUS patients who may be appropriate for novel clinical interventions to prevent progression or eradicate premalignant clones prior to the development of overt MM.
Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory ...cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction VAF ≥2%: odds ratio OR, 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio HR, 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.
•TET2-mutant clonal hematopoiesis is associated with increased risk of incident gout.•Monosodium urate crystal treatment exacerbates Nlrp3-dependent IL-1β secretion and functional impairment in transplanted Tet2-knockout mice.
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Clonal hematopoiesis of indeterminate potential (CHIP)—the age-related clonal expansion of blood stem cells with leukemia-associated mutations—is a novel cardiovascular risk factor. Whether CHIP ...remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear.
This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD.
Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 DNA damage repair genes, and SF3B1/SRSF2/U2AF1 spliceosome genes) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression.
Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001).
CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.
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Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthase. The base excision repair (BER) enzyme uracil-DNA glycosylase (UNG) is the major glycosylase ...responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG(-/-) human colon cancer cells. Here, we examined the relationship between UNG expression and pemetrexed sensitivity in human lung cancer. We observed a spectrum of UNG expression in human lung cancer cells. Higher levels of UNG are associated with pemetrexed resistance and are present in cell lines derived from pemetrexed-resistant histologic subtypes (small cell and squamous cell carcinoma). Acute pemetrexed exposure induces UNG protein and mRNA, consistent with upregulation of uracil-DNA repair machinery. Chronic exposure of H1299 adenocarcinoma cells to increasing pemetrexed concentrations established drug-resistant sublines. Significant induction of UNG protein confirmed upregulation of BER as a feature of acquired pemetrexed resistance. Cotreatment with the BER inhibitor methoxyamine overrides pemetrexed resistance in chronically exposed cells, underscoring the use of BER-directed therapeutics to offset acquired drug resistance. Expression of UNG-directed siRNA and shRNA enhanced sensitivity in A549 and H1975 cells, and in drug-resistant sublines, confirming that UNG upregulation is protective. In human lung cancer, UNG deficiency is associated with pemetrexed-induced retention of uracil in DNA that destabilizes DNA replication forks resulting in DNA double-strand breaks and cell death. Thus, in experimental models, UNG is a critical mediator of pemetrexed sensitivity that warrants evaluation to determine clinical value.
Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart ...failure. This study aimed to test the association of CHIP with new-onset arrhythmias.
UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP variant allele fraction (VAF) ≥ 2%, large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis T1 measured using cardiac magnetic resonance (CMR) were also tested.
This study included 410 702 participants CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%). Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 95% confidence interval (CI) 1.04-1.18; P = .001 and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR.
CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.
Objective
Giant cell arteritis (GCA) is an age‐related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations ...that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood.
Methods
To examine an association between CH and GCA, we analyzed sequenced exomes of 470,960 UK Biobank (UKB) participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations.
Results
UKB participants with CH had a 1.48‐fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (hazard ratio HR 2.98, P = 0.00178) and with TET2 mutation (HR 2.02, P = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, three of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (odds ratio 4.33, P = 0.047).
Conclusions
CH increases risk for development of GCA in a genotype‐specific manner, with the greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA‐associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.
Patients hospitalized with severe acute respiratory syndrome coronavirus 2 infection are at risk for thrombotic complications necessitating use of therapeutic unfractionated heparin (UFH). Full‐dose ...anticoagulation limits requirements for organ support interventions in moderately ill patients with coronavirus disease 2019 (COVID‐19). Given this benefit, it is important to evaluate response to therapeutic anticoagulation in this population.
The aim of this study was to assess therapeutic UFH infusions and associated bleeding risk in patients with COVID‐19.
This retrospective cohort study includes patients at Brigham and Women’s Hospital, Boston, Massachusetts, receiving weight‐based nursing‐nomogram titrated UFH infusion during a 10‐week surge in COVID‐19 hospitalizations. Of 358 patients on therapeutic UFH during this interval, 97 (27.1%) had confirmed COVID‐19. Patient characteristics, laboratory values, and information regarding UFH infusion and bleeding events were obtained from the electronic medical record.
Patients who were COVID‐19 positive had fewer therapeutic activatrd partial thromboplastin times (aPTTs) compared to COVID‐19–negative patients (median rate, 40.0% vs 53.1%; P < .0005). Both major and clinically relevant nonmajor bleeding were increased in COVID‐19–positive patients, with major bleeding observed in 10.3% (95% confidence interval CI, 5.7%‐17.9%) of patients who were COVID‐19 positive and 3.1% (95% CI, 1.6%‐5.9%) of patients who were COVID‐19 negative (P< .005). In logistic regression, bleeding events were associated with receiving UFH for longer than 7 days, but not platelet count, coagulation, or inflammatory measurements.
Our data indicate a higher incidence of bleeding complications in patients with COVID‐19 receiving weight‐based nursing‐nomogram titrated UFH infusions despite a higher prevalence of subtherapeutic aPTTs in this population. These data underscore the need for prospective studies aimed at improving the quality and safety of therapeutic anticoagulation in patients with COVID‐19.
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