Familial Clonal Hematopoiesis in a Long Telomere Syndrome

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 388(26), P. 2422 - 2433

Published: May 4, 2023

Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long length advantageous poorly understood.

Language: Английский

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Genetic basis and molecular profiling in myeloproliferative neoplasms

Blood, Journal Year: 2022, Volume and Issue: 141(16), P. 1909 - 1921

Published: Nov. 8, 2022

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal diseases originating from a single hematopoietic stem cell that cause excessive production of mature blood cells. The 3 subtypes, is, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), diagnosed according to the World Health Organization (WHO) international consensus classification (ICC) criteria. Acquired gain-of-function mutations in 1 disease driver genes (JAK2, CALR, MPL) causative events can alone initiate promote MPN without requiring additional cooperating mutations. JAK2-p.V617F is present >95% PV patients, also about half patients with ET or PMF. PMF caused by CALR MPL. In ∼10% those referred as being "triple negative," none known gene be detected. common theme between triple-negative Janus kinase-signal transducer activator transcription (JAK/STAT) signaling pathway constitutively activated. We review recent advances our understanding early after acquisition mutation. limiting factor determines frequency at which develops long latency not mutations, but rather expansion clone. Factors control conversion hematopoiesis include inherited predisposition, presence inflammation. full extent knowledge mutational landscape individual now increasingly used predict outcome chose optimal therapy.

Language: Английский

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Clonal haematopoiesis and dysregulation of the immune system

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 23(9), P. 595 - 610

Published: March 20, 2023

Language: Английский

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JAK2 V617F allele burden in polycythemia vera: burden of proof

Blood, Journal Year: 2023, Volume and Issue: 141(16), P. 1934 - 1942

Published: Feb. 6, 2023

Polycythemia vera (PV) is a hematopoietic stem cell neoplasm defined by activating somatic mutations in the JAK2 gene and characterized clinically overproduction of red blood cells, platelets, neutrophils; significant burden disease-specific symptoms; high rates vascular events; evolution to myelofibrosis phase or acute leukemia. The JAK2V617F variant allele frequency (VAF) key determinant outcomes PV, including thrombosis myelofibrotic progression. Here, we critically review dynamic role mutation pathogenesis natural history suitability VAF as diagnostic prognostic biomarker, utility reduction PV treatment.

Language: Английский

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Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Nature, Journal Year: 2023, Volume and Issue: 616(7958), P. 755 - 763

Published: April 12, 2023

Language: Английский

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Deciphering cell states and genealogies of human haematopoiesis

Nature, Journal Year: 2024, Volume and Issue: 627(8003), P. 389 - 398

Published: Jan. 22, 2024

Abstract The human blood system is maintained through the differentiation and massive amplification of a limited number long-lived haematopoietic stem cells (HSCs) 1 . Perturbations to this process underlie diverse diseases, but clonal contributions haematopoiesis how changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems 2–5 , simultaneous detection cell states phylogenies natural barcodes humans remains challenging. Here we introduce an improved, single-cell lineage-tracing based on deep naturally occurring mitochondrial DNA mutations readout transcriptional chromatin accessibility. We use define architecture HSCs map physiological state output clones. uncover functional heterogeneity HSC clones, which stable over months manifests as both differences total biases towards production different mature types. also find that diversity clones decreases markedly age, leading oligoclonal structure multiple distinct expansions. Our study thus provides clonally resolved cell-state-aware atlas at resolution, showing unappreciated and, more broadly, paving way for refined dynamics across range tissues health disease.

Language: Английский

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Causes and consequences of clonal hematopoiesis

Blood, Journal Year: 2023, Volume and Issue: 142(26), P. 2235 - 2246

Published: Nov. 6, 2023

Abstract Clonal hematopoiesis (CH) is described as the outsized contribution of expanded clones hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence CH increases dramatically with age. can be caused by somatic mutations in individual genes or gains and/or losses larger chromosomal segments. a premalignant state; detected are initiating for hematologic malignancies, strong predictor development cancers. Moreover, associated nonmalignant disorders increased overall mortality. that drive clonal expansion HSPCs alter function terminally differentiated cells, including release elevated levels inflammatory cytokines. These cytokines may then contribute broad range increase Specific peripheral coordination count parameters powerfully predict malignancies mortality CH. In this review, we summarize current understanding nosology origins. We provide an overview available tools risk stratification discuss management strategies patients presenting hematology clinics.

Language: Английский

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Evolutionary histories of breast cancer and related clones

Nature, Journal Year: 2023, Volume and Issue: 620(7974), P. 607 - 614

Published: July 26, 2023

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated development1-3. However, our knowledge is still missing with regard to what additional driver events take place order, before one or more these tissues ultimately evolve cancer. Here, using phylogenetic analyses multiple microdissected samples from both and non-cancer lesions, we show unique evolutionary histories breast cancers harbouring der(1;16), a alteration found roughly 20% cancers. The approximate timing early was estimated the mutation rate measured epithelial cells. In der(1;16)(+) cancers, derivative chromosome acquired puberty late adolescence, followed by emergence ancestor patient's 30s, evolved. Replacing pre-existing mammary epithelium following years, occupied large area within premenopausal time diagnosis. Evolution independent founders ancestors common, contributing intratumour heterogeneity. number did not correlate histology, suggesting role local microenvironments and/or epigenetic events. A similar pattern also observed another case evolving an AKT1-mutated founder. Taken together, findings provide new insight into how evolves.

Language: Английский

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De novo detection of somatic mutations in high-throughput single-cell profiling data sets

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 42(5), P. 758 - 767

Published: July 6, 2023

Abstract Characterization of somatic mutations at single-cell resolution is essential to study cancer evolution, clonal mosaicism and cell plasticity. Here, we describe SComatic, an algorithm designed for the detection in transcriptomic ATAC-seq (assay transposase-accessible chromatin sequence) data sets directly without requiring matched bulk or DNA sequencing data. SComatic distinguishes from polymorphisms, RNA-editing events artefacts using filters statistical tests parameterized on non-neoplastic samples. Using >2.6 million single cells 688 RNA-seq (scRNA-seq) (scATAC-seq) spanning samples, show that detects accurately, even differentiated polyclonal tissues are not amenable mutation existing methods. Validated against genome scRNA-seq data, achieves F1 scores between 0.6 0.7 across diverse sets, comparison 0.2–0.4 second-best performing method. In summary, permits de novo mutational signature analysis, heterogeneity burdens resolution.

Language: Английский

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Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis

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

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