A5077926033- Acute Lymphoblastic Leukemia research
- Chronic Myeloid Leukemia Treatments
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- CAR-T cell therapy research
- Acute Myeloid Leukemia Research
- Signaling Pathways in Disease
- Pluripotent Stem Cells Research
- Virus-based gene therapy research
- Hematopoietic Stem Cell Transplantation
- Single-cell and spatial transcriptomics
- Mesenchymal stem cell research
- Chronic Lymphocytic Leukemia Research
- CRISPR and Genetic Engineering
- T-cell and Retrovirus Studies
- Developmental Biology and Gene Regulation
- RNA Interference and Gene Delivery
- MicroRNA in disease regulation
- Epigenetics and DNA Methylation
- Bioactive Compounds and Antitumor Agents
- Lung Cancer Research Studies
- Childhood Cancer Survivors' Quality of Life
- Viral gastroenteritis research and epidemiology
- PI3K/AKT/mTOR signaling in cancer
- Microbial Metabolism and Applications
Leiden University Medical Center
2008-2024
Princess Máxima Center
2016-2022
Erasmus MC - Sophia Children’s Hospital
2013-2017
Erasmus University Rotterdam
2014
Erasmus MC
2014
Howard Hughes Medical Institute
2005-2007
Stanford University
2007
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite overall survival 80% in the pediatric setting, 20% patients with T-ALL ultimately die from relapsed or refractory disease. Therefore, there urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to identification recurrent drivers. This review summarizes main drivers targetable lesions gives a...
Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% pediatric cases considered a high-risk disease. T-ALL often associated with resistance to treatment, including steroids, which are currently cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival cure. However, cellular mechanisms underlying patients poorly understood. In this...
We identified mutations in the IL7Ra gene or genes encoding downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN 49% of patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). Strikingly, these (except RAS/NF1) were mutually exclusive, suggesting that they each cause aberrant activation a common target. Expressing mutant molecules-but not their wild-type counterparts-rendered Ba/F3 cells independent IL3 by activating RAS-MEK-ERK PI3K-AKT pathways....
T cell development in the mouse thymus has been studied extensively, but less is known regarding human thymus. We used a combination of single-cell techniques and functional assays to perform deep immune profiling development, focusing on initial stages prelineage commitment. identified three thymus-seeding progenitor populations that also have counterparts bone marrow. In addition, we found physiologically supports monocytes, dendritic cells, NK as well limited B cells. These results are an...
Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human that poorly understood at the molecular level. Here we report translocations targeting zinc finger E-box-binding transcription factor ZEB2 as recurrent genetic lesion in immature/ETP-ALL. Using conditional gain-of-function mouse model, demonstrate sustained Zeb2 expression initiates leukaemia. Moreover, Zeb2-driven exhibit some features immature/ETP-ALL gene signature, well an enhanced leukaemia-initiation potential...
Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early precursor immunophenotype or expression profile, MEF2C-dysregulated cluster based on gene analysis (immature cluster) and retain non-rearranged TRG@ loci. Early exclusively overlap with samples the of signature genes, indicating both are featuring a single disease entity. Patients lacking rearrangements represent only 40% cases, but no further evidence was found to...
Contemporary biomedical research increasingly depends on techniques to induce or inhibit expression of genes in hematopoietic stem cells (HSCs) other primary assess their roles cellular processes including differentiation, apoptosis and migration. Surprisingly little information is available optimize lentiviral transduction HSCs. We have therefore carefully optimized murine human HSCs by optimizing vector design, serum-free virus production quantitation. conclude that the viral RNA length,...
Human T-cell development is less well studied than its murine counterpart due to the lack of genetic tools and difficulty obtaining cells tissues. Here we report transcriptional landscape 11 immature, consecutive human developmental stages. The changes in gene expression cultured stem on OP9-DL1 match those ex vivo isolated thymocytes. These analyses led us define evolutionary conserved signatures that represent pre- post- αβ commitment We found loss dim CD44 marks early CD7+CD5+CD45dim...
Abstract The processes of positive and negative selection in the thymus both determine population T cells that will enter peripheral immune system eliminate self-reactive by apoptosis. Substantial evidence indicates TCR signal intensity mediates this cell fate choice: low-intensity signals lead to survival differentiation, whereas high-intensity generated self-Ag death. molecular mechanism which these graded are converted discrete outcomes is not understood. Positive requires Ca2+-dependent...
Rearrangements that drive ectopic MEF2C expression have recurrently been found in patients with human early thymocyte progenitor acute lymphoblastic leukemia (ETP-ALL). Here, we show high levels of ETP-ALL. Using both vivo and vitro models ETP-ALL, demonstrate elevated blocks NOTCH-induced T cell differentiation while promoting a B-lineage program. activates B transcriptional program addition to RUNX1, GATA3, LMO2; upregulates the IL-7R; boosts survival by upregulation BCL2. Notch pathway,...
Cell fate decisions are orchestrated by an interplay of epigenetic factors in collaboration with transcriptional activators and repressors. The reader MORC3 is known as a silencer endogenous retroviruses mouse embryonic stem cells. Here, we show that expressed the thymus reveal loss function leads to severe arrest T cell development at DN1 stage, accompanied expansion natural killer myeloid depends on its ATPase ability bind H3K4me via CW-type zinc finger domain. We find altered chromatin...
The four Ca(2+)-dependent NFATc proteins are both signal transducers and transcription factors that reside in the cytoplasm until dephosphorylation by calcineurin. Dephosphorylation exposes nuclear import sequences sends into nucleus where they assemble with partners NFAT complexes. Recent genetic studies have indicated calcineurin-NFAT signaling is a major determinant of vertebrate morphogenesis development. Mice lacking calcineurin activity show complete block positive selection CD4 CD8...
Background: The Notch signal transduction pathway is pivotal for various physiological processes, including immune responses, and has been implicated in the pathogenesis of many diseases. effectiveness targeted inhibitors may vary due to variabilities activity among individual patients. quantitative measurement therefore essential identify patients who could benefit from treatment. Methods: We here describe a new assay that infers score mRNA levels generally conserved direct NOTCH target...
The ex vivo expansion and maintenance of long-term hematopoietic stem cells (LT-HSC) is crucial for cell-based gene therapy. A combination cell factor (SCF), thrombopoietin (TPO), FLT3 ligand (FLT3) interleukin 3 (IL3) cytokines has been commonly used in clinical settings the CD34+ from different sources, prior to transplantation. To assess effect IL3 on repopulating capacity cultured cells, we employed STF, TPO FILT3 with or without IL3. Expanded were transplanted into NSG mice, followed by...