Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms DOI Creative Commons
Jing Guo, Klaudia Walter, Pedro M. Quirós

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 17, 2024

Abstract Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2 V617F , common in the population, yet only a minority carriers develop MPN. Here we show that inherited polygenic loci underlie hematological traits influence clonal expansion. We identify risk scores (PGSs) monocyte count and plateletcrit as new factors positivity. PGSs several influenced different MPN subtypes, with low two platelet also showing protective effects carriers, making them to three times less likely have essential thrombocythemia than high PGSs. observed extreme may contribute an diagnosis absence driver mutations. Our study showcases how backgrounds underlying both selection on mutations subsequent phenotype cancer.

Language: Английский

Familial Clonal Hematopoiesis in a Long Telomere Syndrome DOI
Emily A. DeBoy, Michael G. Tassia, Kristen E. Schratz

et al.

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

Citations

90
Genetic basis and molecular profiling in myeloproliferative neoplasms DOI Creative Commons
Damien Luque Paz, Róbert Královics, Radek C. Skoda

et al.

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

Citations

86
Clonal haematopoiesis and dysregulation of the immune system DOI
Roger Belizaire, Waihay J. Wong, Michelle L. Robinette

et al.

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

Published: March 20, 2023

Language: Английский

Citations

72
JAK2 V617F allele burden in polycythemia vera: burden of proof DOI Creative Commons
Alison R. Moliterno, Hannah Kaizer, Brandi Reeves

et al.

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

Citations

61
Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis DOI
Joshua S. Weinstock, Jayakrishnan Gopakumar, Bala Bharathi Burugula

et al.

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

Published: April 12, 2023

Language: Английский

Citations

60
Deciphering cell states and genealogies of human haematopoiesis DOI Creative Commons
Chen Weng, Fulong Yu, Dian Yang

et al.

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

Citations

59
Causes and consequences of clonal hematopoiesis DOI Creative Commons
Lachelle D. Weeks, Benjamin L. Ebert

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

Citations

53
Evolutionary histories of breast cancer and related clones DOI Creative Commons
T Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida

et al.

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

Citations

51
Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis DOI Creative Commons
Nicholas Bernstein, Michael Spencer Chapman, Kudzai Nyamondo

et al.

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

31
Genetic variation across and within individuals DOI
Zhi Yu, Tim H. H. Coorens, Md Mesbah Uddin

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(8), P. 548 - 562

Published: March 28, 2024

Language: Английский

Citations

25