A5015624762- Acute Myeloid Leukemia Research
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- RNA modifications and cancer
- Zebrafish Biomedical Research Applications
- Redox biology and oxidative stress
- Blood disorders and treatments
- Immune Response and Inflammation
- Advanced biosensing and bioanalysis techniques
- Hematopoietic Stem Cell Transplantation
- S100 Proteins and Annexins
- Sulfur Compounds in Biology
- Sarcoma Diagnosis and Treatment
- Hemoglobinopathies and Related Disorders
- Retinoids in leukemia and cellular processes
- Cell Adhesion Molecules Research
- Cancer Genomics and Diagnostics
- Cytokine Signaling Pathways and Interactions
- Immune cells in cancer
- Cancer-related gene regulation
Erasmus MC Cancer Institute
2021-2024
Oncode Institute
2020-2024
Erasmus MC
2012-2023
Erasmus University Rotterdam
2015-2023
Palmetto Hematology Oncology
2019
University Medical Center Freiburg
2019
University Hospital Ulm
2012
Medizinische Hochschule Hannover
2012
Heinrich Heine University Düsseldorf
2012
Düsseldorf University Hospital
2012
Reactive oxygen species (ROS) increase ligation of Fas (CD95), a receptor important for regulation programmed cell death. Glutathionylation reactive cysteines represents an oxidative modification that can be reversed by glutaredoxins (Grxs). The goal this study was to determine whether is redox regulated under physiological conditions. In study, we demonstrate stimulation with ligand (FasL) induces S-glutathionylation at cysteine 294 independently nicotinamide adenine dinucleotide phosphate...
To evaluate the prognostic value of ecotropic viral integration 1 gene (EVI1) overexpression in acute myeloid leukemia (AML) with MLL rearrangements.We identified 286 patients AML t(11q23) enrolled onto German-Austrian Acute Myeloid Leukemia Study Group and Dutch-Belgian-Swiss Hemato-Oncology Cooperative prospective treatment trials. Material was available from 177 for EVI1 expression analysis.We divided MLL-rearranged AMLs into three subgroups: t(9;11)(p22;q23) (44.8%), t(6;11)(q27;q23)...
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...
Acute myeloid leukemia (AML) driven by the activation of
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...
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...
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...
Abstract The first hematopoietic stem cells (HSCs) are formed through endothelial-to-hematopoietic transition (EHT) during embryonic development. transcription factor GATA2 is a crucial regulator of EHT and HSC function throughout life. Because patients with haploinsufficiency have inborn mutations, prenatal defects likely to influence disease In mice, Gata2 (Gata2+/−) reduces the number functionality progenitor (HSPCs) generated EHT. However, HSPC pool heterogeneous mechanisms underlying...
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 The first hematopoietic stem cells (HSCs) are formed through endothelial-to-hematopoietic transition (EHT) events during embryonic development. transcription factor GATA2 is a crucial regulator of EHT and HSC function throughout life. Because haploinsufficiency patients have inborn mutations, prenatal defects likely to an influence on disease In mice, Gata2 ( +/- ) reduces the number functionality progenitor (HSPCs) generated EHT. However, HSPC pool heterogeneous mechanisms...
Background: Chromosomal rearrangements leading to overexpression of EVI1 (MECOM) on chromosome 3q26 define a distinct subtype acute myeloid leukemia (AML) that is associated with chemotherapy resistance and 2-year survival <10%. While genetic events driving aberrant expression are increasingly understood, the molecular functions drive leukemogenesis unclear, which has so far precluded development targeted therapeutics. Aims: We aimed elucidate transcriptional programs maintained by...
Abstract Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable. Since transcription factors like are notoriously hard target, insight into mechanism which drives transformation could provide alternative avenues for therapy. Applying protein folding predictions combined with proteomics technologies, we demonstrate that interaction CTBP1 and CTBP2 via a single PLDLS motif in indispensable leukemic transformation. Furthermore,...