A5017555510- PI3K/AKT/mTOR signaling in cancer
- NF-κB Signaling Pathways
- Viral-associated cancers and disorders
- Chronic Lymphocytic Leukemia Research
- Immune Cell Function and Interaction
- Lymphoma Diagnosis and Treatment
- Cytomegalovirus and herpesvirus research
- CAR-T cell therapy research
- CRISPR and Genetic Engineering
- Histiocytic Disorders and Treatments
- Adenosine and Purinergic Signaling
- Cancer-related molecular mechanisms research
- Neuroendocrine Tumor Research Advances
- Lung Cancer Research Studies
- Autophagy in Disease and Therapy
- Pluripotent Stem Cells Research
- Genetics, Aging, and Longevity in Model Organisms
- Parvovirus B19 Infection Studies
- Innovative Microfluidic and Catalytic Techniques Innovation
- 3D Printing in Biomedical Research
- Eosinophilic Disorders and Syndromes
- RNA modifications and cancer
- Algal biology and biofuel production
- Chronic Myeloid Leukemia Treatments
- Hematopoietic Stem Cell Transplantation
Max Delbrück Center
2013-2024
Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)
2024
Helmholtz Association of German Research Centres
2022
Brigham and Women's Hospital
2011-2019
Office of Infectious Diseases
2012
Harvard University
2011
University of Cincinnati
2011
The CRISPR/Cas9 system is increasingly used for gene inactivation in mouse zygotes, but homology-directed mutagenesis and use of inbred embryos are less established. In particular, Rosa26 knock-in alleles the insertion transgenes a genomic 'safe harbor' site, have not been produced. Here we applied 8–11 kb inserts into C57BL/6 zygotes. We found that 10–20 % live pups derived from microinjected zygotes were founder mutants, without apparent off-target effects, up to 50 recovered upon...
Epstein-Barr virus (EBV) causes Burkitt, Hodgkin, and post-transplant B cell lymphomas. How EBV remodels metabolic pathways to support rapid outgrowth remains largely unknown. To gain insights, primary human cells were profiled by tandem-mass-tag-based proteomics at rest nine time points after infection; >8,000 host 29 viral proteins quantified, revealing mitochondrial remodeling induction of one-carbon (1C) metabolism. EBV-encoded EBNA2 its target MYC required for upregulation the central...
Abstract All cancer cells require increased nutrient uptake to support proliferation. In this study, we investigated the signals that govern glucose in B-cell lymphomas and determined inhibitor of NF-κB-kinase β (IKKβ) induced transporter-1 (GLUT1) membrane trafficking both viral spontaneous lymphomas. IKKβ AKT activity, whereas IKKβ-driven NF-κB transcription was required for GLUT1 surface localization downstream AKT. Activated promoted AKT-mediated phosphorylation regulator, substrate...
Abstract Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) drives viral B cell transformation and oncogenesis. LMP1’s transforming activity depends on its C-terminal activation region 2 (CTAR2), which induces NF-κB JNK by engaging TNF receptor-associated factor 6 (TRAF6). The mechanism of TRAF6 recruitment to LMP1 role in signalling remains elusive. Here we demonstrate that interacts directly with a binding motif within CTAR2. Functional NMR studies supported molecular modeling...
Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, often fatal immune deficiency characterized by severe systemic hyperinflammation. Although allogeneic bone marrow transplantation can be curative, more effective therapies are urgently needed. FHL caused inactivating mutations in proteins that regulate cellular immunity. Here, we used adeno-associated virus–based CRISPR-Cas9 system with inhibitor of nonhomologous end joining to repair such potentially long-lived T cells ex...
Abstract The bloom and bust patterns of microalgae in aquatic systems contribute massively to global biogeochemical cycles. decline algal blooms is mainly caused by nutrient limitation resulting cell death, the arrest division aging surviving cells. Nutrient intake can re-initiate proliferation, but processes involved are poorly understood. Here we characterize how bloom-forming diatom Coscinodiscus radiatus recovers from starvation after influx. Rejuvenation mediated extracellular vesicles...
Introduction Epstein-Barr virus (EBV) infection in humans is associated with a wide range of diseases including malignancies different origins, most prominently B cells. Several EBV latent genes are thought to act together cell immortalization, but minimal set sufficient for transformation remains be identified. Methods Here, we addressed this question by transducing human peripheral cells from EBV-negative donors retrovirus expressing the encoding Latent Membrane Protein (LMP) 1 and 2A...
The described spheroid-on-chip model combines drug testing and immune cell infiltration, allowing the evaluation of novel therapeutic strategies by mimicking targeting complex tumor microenvironment (TME) PDAC.
Abstract Representing the most common malignancy of pancreas, pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type with five-year survival rate less than 13%. To date, targeted treatment regiments are not available, leaving only cytotoxic chemotherapy gemcitabine or FOLFIRINOX as first-line-treatment for patients who ineligible surgical resection. One factor which contributes to lack efficient options presence fibrotic and immunosuppressive tumor microenvironment (TME),...
EBV nuclear antigen 2 (EBNA2) and LP (EBNALP) are critical for B-lymphocyte transformation to lymphoblastoid cell lines (LCLs). EBNA2 activates transcription through recombination signal-binding immunoglobulin κJ region (RBPJ), a factor associated with NCoR repressive complexes, EBNALP is implicated in repressor relocalization. coactivation was found dominate over repression. dismissed NCoR, RBPJ, or from matrix-associated deacetylase (MAD) bodies. In non-EBV-infected BJAB B lymphoma cells...
Significance Epstein–Barr Virus infects human B cells and drives them into proliferation transformation. Although more than 90% of the population is EBV-infected, EBV-driven pathologies including B-cell lymphomas are limited by a potent T-cell immune response. Here, we present mouse model for acute EBV infection through conditional expression two key proteins, LMP1 LMP2A. This reproduces expansion, T-cell–mediated surveillance EBV-infected cells, fatal lymphoproliferative disease when...
Tomoharu Yasuda1, Tristan Wirtz1, Baochun Zhang2, Thomas Wunderlich3, Marc Schmidt-Supprian4, Sommermann1 and Klaus Rajewsky1 1Immune Regulation Cancer, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany 2Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 3Max Planck Institute Neurological Research, 50931 Cologne, 4Max Biochemistry, 82152 Martinsried, Correspondence: klaus.rajewsky{at}mdc-berlin.de tomoharu.yasuda{at}mdc-berlin.de
Mutations accumulating in hematopoietic stem and progenitor cells (HSPCs) during development can cause severe hematological disorders. Modeling these mutations mice is essential for understanding their functional consequences. Here, we describe an efficient CRISPR/Cas9-based system to knock repair genes mouse HSPCs. CRISPR/Cas9 ribonucleoproteins, combination with recombinant adeno-associated virus (rAAV)-DJ donor templates, led gene knockin efficiencies of up 30% the Lmnb1 Actb loci HSPCs...
Epstein-Barr virus (EBV) is a B cell transforming that causes malignancies under conditions of immune suppression. EBV orchestrates transformation through its latent membrane proteins (LMPs) and nuclear antigens (EBNAs). We here identify secondary mutations in mouse lymphomas induced by LMP1, to predict key functions other genes during transformation. find aberrant activation early factor 1 (EBF1) promote LMP1-expressing cells inhibiting their differentiation plasma cells. EBNA3A phenocopies...
Autophagy allows cells to survive under conditions of nutrient deprivation. We have demonstrated that autophagy inhibitors are synthetically lethal with NFκB in B-cell lymphomas because the pathway promotes survival by increasing glucose import. When is inhibited lymphoma, import decreases and become sensitive perturbations mitochondrial metabolism autophagy. Thus, combined inhibition drives into metabolic crisis accelerating cell death.
A highly recurrent somatic L265P mutation in the TIR domain of signaling adapter MYD88 constitutively activates NF-κB. It occurs nearly all human patients with Waldenström’s macroglobulinemia (WM), a B cell malignancy caused by IgM-expressing cells. Here, we introduced an inducible leucine to proline point into mouse Myd88 locus, at orthologous position L252P. When was early during development, cells developed normally. However, plasma accumulated age spleen and bone, leading more than...
Abstract Hematopoiesis is a continuous process of blood cell production driven by hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Proliferation differentiation HSPCs are regulated complex transcriptional networks. In order to identify transcription factors with key roles HSPC-mediated reconstitution, we developed an efficient robust CRISPR/Cas9-based vivo genetic screen. Using this experimental system, identified TFDP1 factor be essential for HSPC proliferation...
<div>Abstract<p>All cancer cells require increased nutrient uptake to support proliferation. In this study, we investigated the signals that govern glucose in B-cell lymphomas and determined inhibitor of NF-κB-kinase β (IKKβ) induced transporter-1 (GLUT1) membrane trafficking both viral spontaneous lymphomas. IKKβ AKT activity, whereas IKKβ-driven NF-κB transcription was required for GLUT1 surface localization downstream AKT. Activated promoted AKT-mediated phosphorylation...
Abstract The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) drives viral B cell transformation and oncogenesis. LMP1's transforming activity depends on its cytoplasmic C-terminal activation region 2 (CTAR2), which induces NF-κB JNK by engaging TNF receptor-associated factor 6 (TRAF6). mechanism TRAF6 interaction with LMP1 critical role for signaling has remained elusive. Here we demonstrate that interacts directly a novel binding motif within CTAR2. Structural modeling...
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