EGAS00001004280-sc-2021-05-07T14:50:43Z - samples
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ABSTRACT:
PROVIDER: EGAD00001007684 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Sequencing of blood stem cell-derived colonies from elderly individuals with clonal haematopoiesis.
| EGAS00001004280 | EGA
Project description:This data presents the transcriptomes of bulk mature colonies derived from single human haematopoietic stem cells / multipotent progenitors (HSC/MPPs) and granulocyte macrophage progenitors (GMPs) purified from one indiviual with age related clonal haematopoisesis. The profiled colonies contain mature monocytes, as measured by conventional cell surface markers (CD14+, CD15-, GlyA-), but no other mature blood cell types. This dataset is part of a larger study, the main objective of which is to understand the functional effects conferred by somatic DNMT3A R882H mutation on human haematopoietic stem cell differentiation capacity. In clonal haematopoiesis, DNMT3A R882H and DNMT3A WT HSPCs co-exist in the same individual. We compared the transcriptional differences between mature monocytic colonies derived from DNMT3A R882H and WT HSPCs in vitro. Analysis of this dataset shows that, in this individual, DNMT3A R882H HSPCs produce less mature monocytes than their WT counterparts over the same culture time.
2023-08-28 | GSE241520 | GEO
Project description:Deep targeted sequencing of 56 genes associated with clonal haematopoiesis and haematological malignancy in peripheral blood-derived DNA from 385 older adults, each sampled 2-5 times over ~13 years.
| EGAD00001007682 | EGA
Project description:Recent epidemiological studies have shown that cancer-associated DNMT3A mutations can be detected in the blood of a large proportion of asymptotic elderly individuals. It is important to understand how these mutations provide a competitive advantage to HSCs and allow them to establish clonal dominance. Here we demonstrate that the stress of serial HSC transplantation immortalizes Dnmt3a-null HSCs.
2018-04-25 | GSE98186 | GEO
Project description:Recent epidemiological studies have shown that cancer-associated DNMT3A mutations can be detected in the blood of a large proportion of asymptotic elderly individuals. It is important to understand how these mutations provide a competitive advantage to HSCs and allow them to establish clonal dominance. Here we demonstrate that the stress of serial HSC transplantation immortalizes Dnmt3a-null HSCs.
2018-04-25 | GSE98185 | GEO
Project description:Recent epidemiological studies have shown that cancer-associated DNMT3A mutations can be detected in the blood of a large proportion of asymptotic elderly individuals. It is important to understand how these mutations provide a competitive advantage to HSCs and allow them to establish clonal dominance. Here we demonstrate that the stress of serial HSC transplantation immortalizes Dnmt3a-null HSCs.
2018-04-25 | GSE98184 | GEO
Project description:Deep targeted sequencing of 56 genes associated with clonal haematopoiesis and haematological malignancy in peripheral blood-derived DNA from 11 older adults, each previously sampled 2-5 times over the preceding ~13 years.
| EGAD00001007683 | EGA
Project description:Human multipotent stromal cells readily form single-cell-derived colonies when plated at clonal densities. However, the colonies are heterogeneous because cells from a colony form new colonies that vary in size and differentiation potential when replated at clonal densities. The experiments here tested the hypothesis that cells in the inner regions of colonies are partially differentiated, but the differentiation is reversible. Cells were separately isolated from the dense inner (IN) regions and less-dense outer regions (OUT) of single-cell-derived colonies. Cells were then compared by assays of their transcriptomes and proteins, and for clonogenicity and differentiation. IN cells expressed fewer cell-cycle genes and higher levels of genes for extracellular matrix than the OUT cells. When transferred to differentiation medium, differentiation of the colonies occurred primarily in the IN regions. However, the IN cells were indistinguishable from OUT cells when replated at clonal densities and assayed for rates of propagation and clonogenicity. Also, colonies formed by IN cells were similar to colonies formed by OUT cells because they had distinct IN and OUT regions. Cultures of IN and OUT cells remained indistinguishable through multiple passages (30-75 population doublings), and both cells formed colonies that were looser and less dense as they were expanded. The results demonstrated that cells in the IN region of single-cell-derived colonies are partially differentiated, but the differentiation can be reversed by replating the cells at clonal densities.
2008-10-07 | GSE13002 | GEO
Project description:Age-related loss of function in the human haematopoietic system is well documented, manifesting as reduced regenerative capacity, age-related cytopenias and immune dysfunction. However, the cellular and population level changes that underpin both this functional decline and the increased risk of clonal haematopoiesis and blood cancer in the elderly remain elusive. Here we performed whole genome sequencing on >3350 single haematopoietic stem cell / multipotent progenitors (HSC/MPP) derived colonies across 10 haematologically normal subjects aged 0 to 81. We found that HSC/MPPs accumulated 17 single nucleotide variants per year post birth and had a reduction in telomere length of 50bp per year throughout young adult life. We reconstructed phylogenies of the sampled HSC/MPPs to interrogate changes in clonal dynamics through life. Haematopoiesis in adults aged less than 65 was predominantly polyclonal, with few known driver mutations. In contrast, individuals aged over 75 displayed a profound change in clonal structure, with frequent clonal expansions, many unexplained by known driver mutations. The ratio of non-synonymous to synonymous mutations revealed widespread positive selection, estimating around 1000 driver mutations in the dataset (10-fold more than the number of known drivers). We identified novel genes ZNF318 and HIST2H3D as being under positive selection, despite not being enriched in myeloid malignancies. Our data show that HSC clonal dynamics is more complex than previously thought. One implication is that by old age, the majority of HSCs carry at least one of a number of largely undescribed driver mutations, which may underlie aspects of their functional decline.
| EGAD00001007851 | EGA
Project description:Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 580,133 somatic mutations from whole-genome sequencing of 1013 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 12 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation driving the majority of these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition from 33 weeks gestation to 10.8 years, in all 5 patients in whom JAK2V617F was either the only or the first driver event. Driver mutations associated with age-related clonal haematopoiesis occurred prior to or following JAK2V617F, as independent clonal expansions in JAK2V617F-mutated patients, and as large clonal expansions in JAK2V617F-unmutated patients . These mutations were also acquired in utero or childhood, with DNMT3A mutations occurring by 8 weeks of gestation to 7.6 years across 4 patients, and PPM1D mutation occurring by age 5.8yrs in a patient with MPN lacking phenotypic driver mutations. Sequential driver mutation acquisition was common, separated by decades across life, and often outcompeted ancestral clones. The mean latency between JAK2V617F acquisition and clinical presentation was 30 years (range 11-54 years). Rates of clonal expansion were inferred from phylogenetic trees and varied substantially (3% to 190% expansion/year), were affected by additional driver mutations, and were predictive of latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition early in life with life-long growth and evolution underlie adult myeloproliferative neoplasms, providing opportunities for early detection and intervention and a new paradigm for cancer development.
| EGAD00001007715 | EGA