Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging
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PROVIDER: EGAS00001007358 | EGA |
REPOSITORIES: EGA
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Project description:Mutations in the nucleophosmin 1 (NPM1) gene are considered as a founder event in the pathogenesis of acute myeloid leukemia (AML). To address the role of clonal evolution in relapsed NPM1 mutated (NPM1mut) AML, we applied high-resolution genome-wide single-nucleotide polymorphism (SNP) array profiling to detect copy number alterations (CNA) and uniparental disomies (UPD) and performed comprehensive gene mutation screening in 53 paired bone marrow/peripheral blood samples obtained at diagnosis and relapse. At diagnosis, 15 aberrations (CNAs, n=10; UPDs, n=5) were identified in 13 patients (25%), whereas at relapse 56 genomic alterations (CNAs, n=46; UPDs, n=10) were detected in 29 patients (55%) indicating an increase in genomic complexity. Recurrent aberrations acquired at relapse included deletions affecting tumor suppressor genes [ETV6 (n=3), TP53 (n=2), NF1 (n=2), WT1 (n=3), FHIT (n=2)] and homozygous FLT3 mutations acquired via UPD13q (n=7). DNMT3A mutations (DNMT3Amut) showed the highest stability (97%). Persistence of DNMT3Amut in 5 patients who lost NPM1mut at relapse suggests that DNMT3Amut may precede NPM1mut in AML pathogenesis. Of note, all relapse samples shared at least one genetic aberration with the matched primary AML sample implying common ancestral clones. In conclusion, our study reveals novel insights into clonal evolution in NPM1mut AML. Bone marrow or peripheral blood samples from diagnosis, remission and relapse of 53 NPM1 mutated AML patient were analyzed on the Affymetrix Genome-Wide Human SNP 6.0 Array. Raw data (CEL-Files) were transformed to genotyping files (CHP) with Genotyping Console Version 4.2 from Affymetrix. Bioinformatic evaluation of CNAs was performed using dChipSNP and circular binary segmentation .
2013-05-30 | E-GEOD-46951 | biostudies-arrayexpress
Project description:Targeted DNA sequencing was performed on 195 bone marrow samples to identify cases of clonal haematopoiesis, and on 99 paired peripheral blood samples. The SeqCap EZ HyperCap protocol was followed, and targeted capture performed against a panel of 97 genes recurrently mutated in myeloid malignancies and clonal hematopoiesis. One BAM file (mapped to the hg38 reference genome) is provided per sample.
| EGAD00001011083 | EGA
Project description:Haematopoeisis emerges in the human fetal bone marrow (BM) at around 12 post conception weeks. This constitutes the second wave of definitive haematopoiesis following on from the first wave in fetal liver from around 6 post conception weeks. The BM emerges as the dominant site of haematopoiesis, responsible for lifelong blood and immune cell production. Yet, little is known about how the composition of the fetal BM, the microenvironment permissive to establishing haematopoiesis and the interplay with other sites of fetal haematopoiesis in fetal health or disease. Herein we utilise single cell RNA sequencing to describe fetal haematopoeisis throughout gestation and better understand the development of the human immune system.
2021-07-15 | E-MTAB-9801 | biostudies-arrayexpress
Project description:Haematopoeisis emerges in the human fetal bone marrow (BM) at around 12 post conception weeks. This constitutes the second wave of definitive haematopoiesis following on from the first wave in fetal liver from around 6 post conception weeks. The BM emerges as the dominant site of haematopoiesis, responsible for lifelong blood and immune cell production. Yet, little is known about how the composition of the fetal BM, the microenvironment permissive to establishing haematopoiesis and the interplay with other sites of fetal haematopoiesis in fetal health or disease. Herein we utilise single cell RNA sequencing to describe fetal haematopoeisis throughout gestation and better understand the development of the human immune system.
2021-07-06 | E-MTAB-9389 | biostudies-arrayexpress
Project description:Haematopoeisis emerges in the human fetal bone marrow (BM) at around 12 post conception weeks. This constitutes the second wave of definitive haematopoiesis following on from the first wave in fetal liver from around 6 post conception weeks. The BM emerges as the dominant site of haematopoiesis, responsible for lifelong blood and immune cell production. Yet, little is known about how the composition of the fetal BM, the microenvironment permissive to establishing haematopoiesis and the interplay with other sites of fetal haematopoiesis in fetal health or disease. Herein we utilise single cell RNA sequencing and surface protein characterisation using CITE-seq technology to describe fetal haematopoeisis throughout gestation and better understand the development of the human immune system.
2021-07-15 | E-MTAB-10042 | biostudies-arrayexpress
Project description:DNA copy number alterations and mutations were characterised by bulk SNP anlaysis and exome sequencing (not sown here) in three acute lymphoblastic leukaemia samples and one establish cell line REH. Further single cell experiments of these cases investigated the mutation and copy number targets previously defined exploring the sub-clonal populations and phylogenic trees within each leukaemia. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples.
2013-07-26 | GSE49215 | GEO
Project description:Somatic mutations in genes implicated in DNA methylation (DNAme; e.g., TET2, DNMT3A and IDH2), are frequently observed in hematological malignancies, as well as in clonal hematopoiesis (CH). Yet, how these mutations disrupt the hematopoietic differentiation topology remains largely unknown. By applying complementary single-cell sequencing approaches to murine bone marrow hematopoietic stem and progenitor cells, we observe that mutations in DNAme modifiers result in significantly altered differentiation topology. In particular, we find shifts in the frequencies of erythroid vs. myelo-monocytic progenitors, which can be traced back to fate-priming skews in the earliest uncommitted hematopoietic stem cells (HSCs). DNAme analysis both in open chromatin regions and at single-cell resolution, demonstrate that methylation changes resulting from DNAme modifier disruption are distributed stochastically across the genome. To reconcile the distributed nature of DNAme changes with the deterministic erythroid vs. myelo-monocytic topological skews, our data implicate differential sensitivity of key transcription factors to global methylation changes due to biases in CpG enrichment in their binding motifs. Finally, by coupling single-cell whole transcriptome analysis with targeted genotyping, we observe a similar skew in early transcriptional priming impact human CH bone marrow progenitors in an individual with DNMT3A-755S mutation. Thus, our results provide evidence that DNAme encodes topological information for hematopoietic differentiation.
2020-02-13 | GSE124822 | GEO
Project description:RNA splicing factors are recurrently affected by alteration-of-function mutations in clonal blood disorders, highlighting the importance of splicing regulation in hematopoiesis. However, our understanding of the impact of dysregulated RNA splicing has been hampered by the inability to distinguish mutant and wildtype cells in primary patient samples, the cell-type complexity of the hematopoietic system, and the sparse coverage of splice junctions by short-read sequencing typically used in single-cell RNA sequencing. To overcome these limitations, we developed GoT-Splice by integrating Genotyping of Transcriptomes (GoT) with enhanced efficiency long-read single-cell transcriptome profiling, as well as proteogenomics (with CITE-seq). This allowed for the simultaneous single-cell profiling of gene expression, cell surface protein markers, somatic mutation status, and RNA splicing. We applied GoT-Splice to bone marrow progenitors from patients with myelodysplastic syndrome (MDS) affected by mutations in the most prevalent mutated RNA splicing factor – the core RNA splicing factor SF3B1. High-resolution mapping of SF3B1mut vs. SF3B1wt hematopoietic progenitors revealed increased fitness advantage of SF3B1mut cells in the megakaryocytic-erythroid lineage, resulting in an expansion of SF3B1mut erythroid progenitor (EP) cells. SF3B1mut EP cells exhibited upregulation of genes involved in regulation of cell cycle and mRNA translation. Long-read single-cell transcriptomes revealed the previously reported increase of aberrant 3’ splicing site usage in SF3B1mut cells. However, the ability to profile splicing within individual cell populations uncovered distinct cryptic 3’ splice site usage across different progenitor populations, as well as stage-specific aberrant splicing during erythroid maturation. Lastly, as splice factor mutations occur in clonal hematopoiesis (CH) with increased risk of neoplastic transformation, we applied GoT-Splice to CH samples. These data revealed that the erythroid lineage bias, as well as cell-type specific cryptic 3’ splice site usage in SF3B1mut cells, precede overt MDS. Collectively, we present an expanded multi-omics single-cell toolkit to define the cell-type specific impact of somatic mutations on RNA splicing, from the earliest phases of clonal outgrowths to overt neoplasia, directly in human samples.
2023-08-14 | GSE204845 | GEO
Project description:Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.
2023-03-27 | GSE227690 | GEO
Project description:Single cell analysis of emergent haematopoiesis in the human fetal bone marrow
| PRJEB42709 | ENA