A5035663099- Acute Myeloid Leukemia Research
- Immune Response and Inflammation
- RNA Interference and Gene Delivery
- Cell death mechanisms and regulation
- NF-κB Signaling Pathways
- Acute Lymphoblastic Leukemia research
- Protein Degradation and Inhibitors
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Histone Deacetylase Inhibitors Research
- Cytokine Signaling Pathways and Interactions
- Chronic Myeloid Leukemia Treatments
- Advanced biosensing and bioanalysis techniques
- Psoriasis: Treatment and Pathogenesis
- Epigenetics and DNA Methylation
- Autoimmune Bullous Skin Diseases
- Cell Adhesion Molecules Research
- Dermatologic Treatments and Research
- Systemic Sclerosis and Related Diseases
- Chronic Lymphocytic Leukemia Research
- Protein Kinase Regulation and GTPase Signaling
- Sarcoma Diagnosis and Treatment
- interferon and immune responses
- Cancer-related Molecular Pathways
Princess Máxima Center
2019-2025
University Medical Center Utrecht
2024
Center for Translational Molecular Medicine
2024
Newcastle University
2008-2017
NIHR Oxford Musculoskeletal Biomedical Research Centre
2011-2013
University of Stuttgart
2002-2010
Heidelberg University
2009
Fraunhofer Institute for Interfacial Engineering and Biotechnology
2005
Medizinische Hochschule Hannover
2000-2001
Abstract UBTF tandem duplications (UBTF-TDs) have recently emerged as a recurrent alteration in pediatric and adult acute myeloid leukemia (AML). UBTF-TD leukemias are characterized by poor response to conventional chemotherapy transcriptional signature that mirrors NUP98-rearranged NPM1-mutant AMLs, including HOX-gene dysregulation. However, the mechanism which drives leukemogenesis remains unknown. In this study, we investigated genomic occupancy of transformed cord blood CD34+ cells...
Abstract Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option still chemotherapy targets such However, patients harbour quiescent leukemic stem cells (LSCs) can emerge from quiescence trigger...
Abstract The capacity of dendritic cells (DC) to regulate adaptive immunity is controlled by their maturation state and lifespan. Although TNF a well-known survival factor for DC, the role two TNFR, TNFR1 TNFR2, in mediating these effects poorly understood. By using unique variants that selectively signal through and/or we demonstrate differential functions TNFR human monocyte-derived blood CD1c+ DC. Activation TNFR1, but not efficiently induced DC maturation, as defined enhanced expression...
Chromosomal translocations involving the
Max is the central component of Myc/Max/Mad network transcription factors that regulate growth, differentiation and apoptosis. Whereas Myc Mad genes proteins are highly regulated, expression constitutive no post-translational regulation known. We have found targeted during Fas-induced first dephosphorylated subsequently cleaved by caspases. Two specific cleavage sites for caspases in were identified, one at IEVE(10) decreasing S SAFD(135) G near C-terminus, which vitro caspase-5 caspase-7...
In an attempt to improve TRAIL's (tumor necrosis factor-related apoptosis-inducing ligand) tumor selective activity a variant was designed, in which the three TRAIL protomers are expressed as single polypeptide chain (scTRAIL). By genetic fusion with single-chain antibody fragment (scFv) recognizing extracellular domain of ErbB2, we further equipped scTRAIL tumor-targeting properties. We studied targeting and apoptosis induction scFv-scTRAIL comparison non-targeted scTRAIL. Importantly,...
Abstract Objective The role of tumor necrosis factor (TNF) in systemic sclerosis (SSc) remains controversial. present study was undertaken to investigate the influence TNF receptor (TNFR)–costimulated lymphocytes on collagen expression fibroblasts. Methods TNFR mononuclear cells from dermis and blood SSc patients assessed by flow cytometry. Peripheral CD3+ were activated with CD3/CD28 beads costimulated TNFR‐selective variants. Expression interleukin‐6 (IL‐6), soluble IL‐6 (sIL‐6R), IL‐10,...
Tumor necrosis factor (TNF) exists both as a membrane-integrated type II precursor protein and soluble cytokine that have different bioactivities on TNFR2 (CD120b) but not TNFR1 (CD120a). To identify the molecular basis of this disparity, we investigated receptor chimeras comprising cytoplasmic part Fas (CD95) extracellular domains two TNF receptors. The membrane form TNF, its form, was capable inducing apoptosis well activation c-Jun N-terminal kinase NF-κB via TNFR2-derived chimera. In...
The inflammatory and proapoptotic cytokine TNF possesses a compelling potential as an antitumoral therapeutic agent. Possible target cells include the malignant themselves, tumor vasculature, or immune system. As clinical use of is limited by systemic toxicity, targeting strategies using TNF-based fusion proteins are currently used. A major obstacle, however, that homotrimeric ligands prone to activity loss due dissociation into their monomers. In this study, we report construction...
The family of tumor necrosis factor receptors (TNFRs) and their ligands form a regulatory signaling network that controls immune responses. Various members this receptor respond differently to the soluble membrane-bound forms respective ligands. However, determining factors underlying molecular mechanisms diversity are not yet understood. Using an established system chimeric TNFRs novel ligand variants mimicking bioactivity TNF (mTNF), we demonstrate membrane-proximal extracellular stalk...
Max is the central component of Myc/Max/Mad network transcription factors that regulate growth, differentiation and apoptosis. Whereas Myc Mad genes proteins are highly regulated, expression constitutive no post-translational regulation known. We have found targeted during Fas-induced first dephosphorylated subsequently cleaved by caspases. Two specific cleavage sites for caspases in were identified, one at IEVE10↓S SAFD135↓G near C-terminus, which vitro caspase-5 caspase-7 respectively....
Cellular apoptosis, the prototype of programmed cell death, can be induced by activation so-called death receptors. Interestingly, soluble and membrane-bound members receptor ligands differentially activate their Using ligand tumor necrosis factor (TNF) presented on a surface in nanoscaled pattern with spacings between 58 290 nm, we investigated its requirements for spatial arrangement motility to efficiently TNF (TNFR)1 TNFR2 as well chimeras TNFR1-Fas TNFR2-Fas. We show that mere...
T-cell Acute Lymphoblastic Leukemia (T-ALL) is frequently characterized by glucocorticoid (GC) resistance, which associated with inferior outcomes, thus highlighting the need for novel therapeutic approaches GC resistant T-ALL. The pTCR/TCR signaling pathways play a critical role in cell fate decisions during physiological thymocyte development, an interplay between TCR and receptor (GR) determining T-lymphocyte selection process. We performed shRNA screen vitro vivo T-ALL lines patient...
Lipid nanoparticles (LNPs) have evolved rapidly as promising delivery systems for oligonucleotides, including siRNAs. However, current clinical LNP formulations show high liver accumulation after systemic administration, which is unfavorable the treatment of extrahepatic diseases, such hematological disorders. Here we describe specific targeting LNPs to hematopoietic progenitor cells in bone marrow. Functionalization with a modified Leu-Asp-Val tripeptide, ligand very-late antigen 4 resulted...
Chromosomal rearrangements that generate novel fusion genes are a hallmark of acute myeloid leukemia (AML). Depletion experiments in cell line models have suggested continued expression is required for maintaining their leukemic phenotype and they therefore represent ideal cancer-specific therapeutic targets. However, to which extent this result holds true the different stages hematopoietic development primary cells whether agents can be efficiently delivered those still unclear. In study,...
Mad1 is a member of the Myc/Max/Mad network transcriptional regulators that play central role in control cellular behavior. Mad proteins are thought to antagonize Myc functions at least part by repressing gene transcription. To systematically examine function growth and during apoptosis, we have generated U2OS cell clones express under tetracyline-regulatable promoter (UTA-Mad1). was induced rapidly efficiently, localized nucleus, bound DNA as heterodimer with Max. The induction reduced and,...
The transcriptional regulator Yin Yang 1 (YY1) controls many aspects of cell behavior and is essential for development. We analyzed the fate YY1 during apoptosis studied functional consequences. observed that this factor rapidly translocated into nucleus in response to various apoptotic stimuli, including activation Fas, stimulation by tumor necrosis factor, staurosporine etoposide treatment. Furthermore, cleaved caspases vitro vivo at two distinct sites, IATD(12)G DDSD(119)G, resulting...