Blood, Journal Year: 2021, Volume and Issue: 137(21), P. 2992 - 2997
Published: Feb. 18, 2021
Language: Английский
Nature, Journal Year: 2022, Volume and Issue: 606(7913), P. 343 - 350
Published: June 1, 2022
Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity 1 , cytopenias 2 immune dysfunction 3 and increased risk of blood cancer 4–6 but the reason for such abrupt functional decline after 70 years age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies haematopoietic cells across 10 subjects 0 to 81 age. Haematopoietic stem or multipotent progenitors (HSC/MPPs) accumulated a mean 17 mutations per year birth lost 30 base pairs telomere length. Haematopoiesis adults less than 65 was massively polyclonal, with high clonal diversity stable population 20,000–200,000 HSC/MPPs contributing evenly production. By contrast, individuals aged over 75 showed profoundly decreased diversity. In each older subjects, 30–60% accounted by 12–18 independent clones, 1–34% Most clones had begun their expansion before subject 40 old, only 22% known driver mutations. Genome-wide selection analysis estimated that between 34 12 non-synonymous were drivers, accruing at constant rates throughout life, affecting more genes identified cancers. Loss Y chromosome conferred selective benefits males. Simulations haematopoiesis, cell size acquisition conferring moderate fitness benefits, entirely explained structure elderly. Rapidly decreasing is universal feature humans, underpinned pervasive positive acting on many currently identified.
Language: Английский
Citations
329
Nature, Journal Year: 2022, Volume and Issue: 612(7939), P. 301 - 309
Published: Nov. 30, 2022
Language: Английский
Citations
189
Blood, Journal Year: 2023, Volume and Issue: unknown
Published: Jan. 18, 2023
Language: Английский
Citations
90
Nature Genetics, Journal Year: 2024, Volume and Issue: 56(6), P. 1147 - 1155
Published: May 14, 2024
Abstract Human aging is marked by the emergence of a tapestry clonal expansions in dividing tissues, particularly evident blood as hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations set established genes. However, majority clones lack known drivers. Here we infer gene-level positive selection whole exomes 200,618 individuals UK Biobank. We identify 17 additional genes, ZBTB33 , ZNF318 ZNF234 SPRED2 SH2B3 SRCAP SIK3 SRSF1 CHEK2 CCDC115 CCL22 BAX YLPM1 MYD88 MTA2 MAGEC3 IGLL5 under at population level, validate this pattern 10,837 genomes single-cell-derived hematopoietic colonies. Clones with these genes grow frequency size age, comparable classical CH They correlate heightened infection, death hematological malignancy, highlighting significance process.
Language: Английский
Citations
28
New England Journal of Medicine, Journal Year: 2025, Volume and Issue: 392(16), P. 1594 - 1608
Published: April 23, 2025
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients cancer. CHIP mutations high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal (TI-CH). The frequency TI-CH and its effect on tumor evolution are unclear. We characterized 421 early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study 49,351 MSK-IMPACT pan-cancer cohort. studied association survival disease recurrence evaluated functional TET2-mutant biologic features tumors. Among NSCLC, 42% those had TI-CH. independently predicted risk death or recurrence, adjusted hazard ratio 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared absence 1.62 CI, 1.02 2.56) solid 26% conferred any cause that was 1.17 times 1.06 1.29) TET2 were strongest genetic predictor TI-CH; such enhanced monocyte migration cells, fueled myeloid-rich microenvironment mice, resulted promotion organoid growth. NSCLC remodeled immune accelerated growth, findings support role for aging-related hematologic proliferation evolution. (Funded by Royal Society others.).
Language: Английский
Citations
2
Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)
Published: July 23, 2022
Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) drive clonal hematopoiesis (CH). While some CH drivers have been identified, the compendium of all able upon mutations HSCs remains incomplete. Exploiting signals positive selection blood somatic may be an effective way identify driver genes, analogously cancer. Using tumor sample blood/tumor pairs as reference, we across more than 12,000 donors from two large cancer genomics cohorts. The application IntOGen, discovery pipeline, both cohorts, and 24,000 targeted sequenced samples yields list close 70 with CH, available at http://www.intogen.org/ch . This approach recovers known discovers other candidates.
Language: Английский
Citations
66
Nature Genetics, Journal Year: 2023, Volume and Issue: 55(12), P. 2149 - 2159
Published: Nov. 6, 2023
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from single hematopoietic stem cell lineage. Using whole-genome sequencing 45,510 Icelandic and 130,709 UK Biobank participants combined with mutational barcode method, we identified 16,306 people CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates dosage-dependent impact on risk CH associates several smoking-related diseases. Contrary to published claims, find no evidence that associated cardiovascular disease. We provide driven by genes are commonly mutated myeloid neoplasia implicate new driver genes. The presence nature mutation alters the profile for hematological disorders. Nevertheless, most cases have known mutations. A genome-wide association study 25 loci, including 19 not implicated previously Splicing, protein expression quantitative trait loci were CD164 TCL1A.
Language: Английский
Citations
41
Circulation, Journal Year: 2023, Volume and Issue: 148(15), P. 1165 - 1178
Published: Sept. 8, 2023
Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, has been associated with worse outcomes in patients heart failure (HF) reduced ejection fraction. However, the role CH prognosis HF preserved fraction (HFpEF) understudied. This study aimed characterize HFpEF elucidate its causal a murine model.
Language: Английский
Citations
33
Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(4), P. 844 - 857
Published: Feb. 8, 2023
Abstract We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors pediatric cancer with a median follow-up time 23.5 years. Deep sequencing over 39 CH-related genes reveals mutations 15% survivors, significantly higher than 8.5% 324 community controls. CH is associated exposures to alkylating agents, radiation, and bleomycin. Therapy-related shows significant enrichment STAT3, characterized as gene specific Hodgkin lymphoma, TP53. Single-cell profiling peripheral blood samples revealed STAT3 predominantly T cells contributed by SBS25, mutational signature procarbazine exposure. Serial sample tracking that larger clone size predictor for future expansion age-related clones, whereas therapy-related remains stable decades after treatment. These data depict distinct dynamics these subtypes support need longitudinal monitoring determine potential contribution late effects. Significance: This analysis presents elevated prevalence therapy exposures/diagnostic spectrum CH. Due contrasting versus CH, recommended ascertain effects therapy-induced survivors. See related commentary Collord Behjati, p. 811. article highlighted In Issue feature, 799
Language: Английский
Citations
30
Blood, Journal Year: 2023, Volume and Issue: unknown
Published: Jan. 10, 2023
Language: Английский
Citations
27