A5004454425- Cancer Research and Treatments
- Acute Myeloid Leukemia Research
- Cancer Genomics and Diagnostics
- CRISPR and Genetic Engineering
- Chromosomal and Genetic Variations
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Genetic Mapping and Diversity in Plants and Animals
- Hemoglobinopathies and Related Disorders
- Plant Genetic and Mutation Studies
- Renal and related cancers
- Cancer Cells and Metastasis
- Hematological disorders and diagnostics
- Single-cell and spatial transcriptomics
- Pharmacogenetics and Drug Metabolism
- Computational Drug Discovery Methods
- Epigenetics and DNA Methylation
- RNA regulation and disease
- Chronic Myeloid Leukemia Treatments
- Plant tissue culture and regeneration
- Pluripotent Stem Cells Research
- Virus-based gene therapy research
- Synthesis and biological activity
- Genetic factors in colorectal cancer
- Soybean genetics and cultivation
- Animal Genetics and Reproduction
Princess Máxima Center
2018-2024
Oncode Institute
2020-2024
Royal Netherlands Academy of Arts and Sciences
2021
University of Amsterdam
2016-2018
Netherlands Institute for Neuroscience
2017
Lund University
2012
AstraZeneca (Sweden)
2012
Previous studies have described that tumor organoids can capture the diversity of defined human carcinoma types. Here, we describe conditions for long-term culture mucosal organoids. Using this protocol, a panel 31 head and neck squamous cell (HNSCC)-derived organoid lines was established. This recapitulates genetic molecular characteristics previously HNSCC. Organoids retain their tumorigenic potential upon xenotransplantation. We observe differential responses to drugs including cisplatin,...
Abstract Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs livers mice cynomolgus macaques for reduction blood low-density lipoprotein (LDL) levels. Lipid nanoparticle–based delivery mRNA encoding an ABE a single-guide RNA targeting PCSK9 , negative regulator LDL, induced up 67% editing (on average, 61%) 34% 26%) macaques. Plasma LDL levels...
Abstract Kidney tumours are among the most common solid in children, comprising distinct subtypes differing many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing disease heterogeneity currently lacking. Here, we describe first paediatric cancer organoid biobank. It contains tumour matching normal kidney organoids from over 50 children with different of cancer, Wilms tumours, malignant rhabdoid renal carcinomas, congenital mesoblastic nephromas....
Mutation accumulation during life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Somatic mutations in blood progenitors provide insight into rate and processes this accumulation, as well developmental lineage tree stem cell division numbers. Here, we catalog genomes of human-bone-marrow-derived umbilical-cord-blood-derived progenitor cells (HSPCs). We find that accumulate gradually with approximately 14 base substitutions per year. The majority...
Abstract Prime editing is a recent genome technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct the vast majority genetic defects. Here, we develop prime for primary adult stem cells grown in organoid culture models. First, generate precise in-frame deletions gene encoding β‐catenin ( CTNNB1 ) result proliferation independent Wnt-stimuli, mimicking mechanism development liver cancer. Moreover, functionally recovers disease-causing mutations...
The collective of somatic mutations in a genome represents record mutational processes that have been operative cell. These can be investigated by extracting relevant patterns from sequencing data.
Prime editing is a recently reported genome tool using nickase-cas9 fused to reverse transcriptase that directly synthesizes the desired edit at target site. Here, we explore use of prime in human organoids. Common TP53 mutations can be correctly modeled adult stem cell-derived colonic organoids with efficiencies up 25% and 97% hepatocyte Next, functionally repaired cystic fibrosis CFTR-F508del mutation compared CRISPR/Cas9-mediated homology-directed repair adenine base on CFTR-R785*...
While most cells in multicellular organisms carry the same genetic information, each cell type only a subset of genes is being transcribed. Such differentiation gene expression depends, for large part, on activation and repression regulatory sequences, including transcriptional enhancers. Transcriptional enhancers can be located tens kilobases from their target genes, but display characteristic chromatin DNA features, allowing identification by genome-wide profiling. Here we show that...
Despite the importance and wide exploitation of heterosis in commercial crop breeding, molecular mechanisms behind this phenomenon are not completely understood. Recent studies have implicated changes DNA methylation small RNAs hybrid performance; however, it remains unclear whether epigenetic a cause or consequence heterosis. Here, we analyze large panel over 500 Arabidopsis (Arabidopsis thaliana) plants (epiHybrids), which derived from near-isogenic but epigenetically divergent parents....
Genetic instability is a major concern for successful application of stem cells in regenerative medicine. However, the mutational consequences most applied cell therapy humans, hematopoietic transplantation (HSCT), remain unknown. Here we characterized mutation burden and progenitor (HSPCs) human HSCT recipients their donors using whole-genome sequencing. We demonstrate that majority transplanted HSPCs did not display altered accumulation. some recipients, identified multiple with an...
Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes the mutation burden and clonal composition of healthy tissues early in life. Here, we studied accumulation hematopoietic stem progenitor cells (HSPC) before after treatment 24 children. Of these children, 19 developed myeloid neoplasms (t-MN). Posttreatment HSPCs had an average increase comparable what...
Significance The collection of large amounts whole-genome sequencing data allowed for identification mutational signatures, which are characteristic combinations substitutions in the context neighboring bases. clinical significance these signatures is still largely unknown. In neuroblastoma, we showed that high levels cytosine > adenine (C A) associated with poor survival. We identified C A result from defects 8-oxo-guanine repair, specifically copy number loss DNA glycosylases MUTYH and...
Abstract Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence leukemia in children higher than young adults. Here we compare somatic across pediatric acute myeloid (pAML) patient-matched leukemic blasts and hematopoietic stem progenitor cells (HSPC), as well HSPCs from age-matched healthy donors. bone marrow have limited genetic relatedness share few cell origin malignant blasts, suggesting polyclonal hematopoiesis patients...
By replicating damaged nucleotides, error-prone DNA translesion synthesis (TLS) enables the completion of replication, albeit at expense fidelity. TLS helix-distorting lesions, that usually have reduced capacity basepairing, comprises insertion opposite lesion followed by extension, latter in particular polymerase ζ (Pol ζ). However, little is known about involvement Pol non- or poorly-distorting, but miscoding, lesions such as O
Significance Barrett’s esophagus (BE), the premalignant condition of esophageal adenocarcinoma, is categorized into different stages which correlate with risk developing carcinoma. We performed single-cell DNA-sequencing experiments fresh biopsies, revealed appearance a specific T > C and G mutational signature, known as COSMIC signature SBS17, in BE cells that are chromosomally unstable. The SBS17-specific mutations were, however, not detected stable cells. Additionally, we RNA...
Carcinogenesis results from the sequential acquisition of oncogenic mutations that convert normal cells into invasive, metastasizing cancer cells. Colorectal exemplifies this process through its well-described adenoma-carcinoma sequence, modeled previously using clustered regularly interspaced short palindromic repeats (CRISPR) to induce four consecutive in wild-type human gut organoids. Here, we demonstrate long-term culture mismatch-repair-deficient organoids allows selection spontaneous...
Abstract Prime editing is a novel genome technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct the vast majority genetic defects. We develop prime for primary adult stem cells grown in organoid culture models. First, we generate precise in-frame deletions gene encoding ß-catenin ( CTNNB1 ) result proliferation independent Wnt-stimuli, mimicking mechanism development liver cancer. Moreover, functionally recovers diseasecausing mutations...
Abstract Background The collective of somatic mutations in a genome represents record mutational processes that have been operative cell. These can be investigated by extracting relevant patterns from sequencing data. Results Here, we present the next version MutationalPatterns, an R/Bioconductor package, which allows in-depth analysis catalogues single and double base substitutions as well small insertions deletions. Major features package include possibility to perform regional mutation...
Hematopoietic stem and progenitor cells (HSPCs) gradually accumulate DNA mutations during a lifespan, which can contribute to age-associated diseases such as leukemia. Characterizing mutation accumulation improve understanding of the etiology diseases. Presented here is method catalogue somatic in individual HSPCs, based on whole-genome sequencing (WGS) clonal primary cell cultures. Mutations that are present original shared by all culture, whereas acquired vitro after sorting subset cells....