A5077265649- Acute Myeloid Leukemia Research
- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- Histone Deacetylase Inhibitors Research
- Cancer Genomics and Diagnostics
- Cancer-related gene regulation
- RNA Research and Splicing
- Blood disorders and treatments
- Angiogenesis and VEGF in Cancer
- Metabolomics and Mass Spectrometry Studies
- Congenital heart defects research
- CRISPR and Genetic Engineering
- Genomic variations and chromosomal abnormalities
- Bioinformatics and Genomic Networks
- Genomics and Phylogenetic Studies
- Diet and metabolism studies
- Cholesterol and Lipid Metabolism
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Genetic Associations and Epidemiology
- Alzheimer's disease research and treatments
- Immune Response and Inflammation
- Cholinesterase and Neurodegenerative Diseases
Erasmus MC
2018-2025
Erasmus MC Cancer Institute
2021-2025
Erasmus University Rotterdam
2018-2025
Rotterdam University of Applied Sciences
2025
Oncode Institute
2020-2024
Institute for Molecular Medicine Finland
2021
University of Helsinki
2021
Statistics Finland
2021
Anaxomics (Spain)
2014-2017
Universitat Autònoma de Barcelona
2017
Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression EVI1 is found subgroup acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which often therapy resistant. In AMLs harboring t(3;8)(q26;q24), we observed the translocation MYC super-enhancer (MYC SE) to locus. We generated an vitro model mimicking patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation by hijacked SE. This SE...
Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2, but not its paralog STAG1, are frequently mutated in myeloid malignancies. To elucidate underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, transcriptional, and conformational changes acute leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression, local activation, which were compensated by remaining...
Acute myeloid leukemia (AML) driven by the activation of
Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in an aggressive subtype of acute myeloid leukemia (AML). Direct depletion using endogenous auxin-inducible degron immediately upregulates differentiation factor CEBPA. is also accompanied by a severe loss stem cells and gain differentiation. exerts its inhibitory effect binding the +42kb CEBPA enhancer, gene essential for neutrophil development. This partially dependent on interaction between...
Abstract X-chromosome inactivation (XCI) is initiated during early mammalian embryogenesis by a long non-coding RNA (lncRNA) XIST , which coats one of the two X-chromosomes and facilitates epigenetic transcriptional silencing. A second, evolutionarily recent primate-specific lncRNA XACT was proposed to antagonize ’s ability induce XCI. expression restricted pluripotent states embryonic stages active in both females males. Here, we report novel transcript expressed normal cancerous somatic...
The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the gene drive severe hematologic abnormalities and are associated with an increased risk myelodysplastic syndromes acute myeloid leukemia; however, mechanisms underlying pathophysiology deficiency remain still unclear. We developed two different mouse models that based on serial limiting donor cell transplantation (aged) haploinsufficient cells mirror symptoms deficiency. Similar to what has been observed...
Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. Genomic rearrangements that reposition active enhancers near proto-oncogenes, leading to their aberrant expression, have not been systematically investigated in AML. To facilitate the discovery of such "enhancer hijacking" events, we developed pyjacker, a computational tool, applied it 39 ckAML samples. Pyjacker identified several enhancer...
Abstract In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied unbiased CRISPR/Cas9 scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpointed single regulatory element in the that is critically required aberrant expression. This contained DNA-binding motif transcription factor MYB, which specifically occupied site at...
Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there no effective treatment. One the main difficulties in developing new therapies lies on multiple events that contribute to death amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome synaptic...
The 1000 Genomes Project (1000GP) represents the most comprehensive world-wide nucleotide variation data set so far in humans, providing sequencing and analysis of 2504 genomes from 26 populations reporting >84 million variants. availability this sequence provides human lineage with an invaluable resource for population genomics studies, allowing testing molecular genetics hypotheses eventually understanding evolutionary dynamics genetic populations. Here we present PopHuman, a new...
Detailed genomic and epigenomic analyses of MECOM (the MDS1 EVI1 complex locus) have revealed that inversion or translocation chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement an enhancer upregulates transcription EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform is frequently present in acute leukemia (AML) directly contributes to leukemic transformation. This generated by mutations the core RNA splicing factor...
Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. developed pyjacker, a computational tool for detection of enhancer hijacking events, applied it cohort 39 ckAML samples. Pyjacker identified motor neuron pancreas homeobox 1 (MNX1), gene aberrantly...
Mono-allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), affecting more than 85% carriers. How partial loss functionality enables leukemic transformation years later is unclear. This question has remained unsolved mainly due to lack informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different mutations (TgErg/Gata2het...
The transcription factor C/EBPa initiates the neutrophil gene expression program in bone marrow (BM). Knockouts of Cebpa or its +37kb enhancer mice show 2 major findings: (1) neutropenia BM and blood; (2) decrease long-term hematopoietic stem cell (LT-HSC) numbers. Whether latter finding is cell-autonomous (intrinsic) to LT-HSCs an extrinsic event exerted on compartment remained open question. Flow cytometric analysis knockout model revealed that reduction LT-HSC numbers observed was...
Abstract Epithelial ovarian cancer (OC) is typically diagnosed at a late stage and, despite treatment with cytoreductive surgery and chemotherapy, 70-80% of patients relapse eventually die due to the disease. Major challenges improve patient outcomes are overcome therapy resistance individually tailor therapy. Uncovering molecular drivers OC, especially in most common subgroup high-grade serous (HGS), will help develop novel therapeutic strategies meet these challenges. Using Cancer Genome...
Abstract Leukemias with ambiguous lineage comprise several loosely defined entities, often without a clear mechanistic basis. Here, we extensively profile the epigenome and transcriptome of subgroup such leukemias CpG Island Methylator Phenotype. These exhibit comparable hybrid myeloid/lymphoid epigenetic landscapes, yet heterogeneous genetic alterations, suggesting they are by their shared rather than common lesions. Gene expression enrichment reveals similarity early T-cell precursor acute...
The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the gene drive severe hematologic abnormalities and are associated with an increased risk myelodysplastic syndromes acute myeloid leukemia; however, mechanisms underlying pathophysiology deficiency remain still unclear. We developed two different mouse models that based on serial limiting donor cell transplantation (aged) haploinsufficient cells mirror symptoms deficiency. Similar to what has been observed...