A5044132744- Acute Myeloid Leukemia Research
- Virus-based gene therapy research
- CAR-T cell therapy research
- Protein Degradation and Inhibitors
- Chronic Myeloid Leukemia Treatments
- Viral Infectious Diseases and Gene Expression in Insects
- CRISPR and Genetic Engineering
- Immune cells in cancer
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Phagocytosis and Immune Regulation
- Viral Infections and Immunology Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Hematopoietic Stem Cell Transplantation
- Epigenetics and DNA Methylation
- Immune Cell Function and Interaction
- Immune Response and Inflammation
- Hemoglobinopathies and Related Disorders
- Blood disorders and treatments
- Animal Genetics and Reproduction
- Genomics and Chromatin Dynamics
- Cell Adhesion Molecules Research
- Animal Virus Infections Studies
- RNA Interference and Gene Delivery
Ludwig-Maximilians-Universität München
2013-2024
Georg Speyer Haus
2008-2016
CTI BioPharma (United Kingdom)
2014
Abstract The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results RUNX1 / RUNX1T1 rearrangement. Despite causative role fusion gene initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations 23% (13/56) AML patients, including missense truncating resulting alteration or loss C-terminal zinc-finger domain ZBTB7A. transcription factor important haematopoietic...
The RUNX1/ETO (RE) fusion protein, which originates from the t(8;21) chromosomal rearrangement, is one of most frequent translocation products found in de novo acute myeloid leukemia (AML). In RE leukemias, activated forms c-KIT tyrosine kinase receptor are frequently found, thereby suggesting oncogenic cooperativity between these oncoproteins development and maintenance malignancies. this report, we show that cooperates with a C-terminal truncated variant RE, REtr, to expand human CD34+...
Comparative integrome analysis has revealed that the most neutral integration pattern among retroviruses is attributed to alpharetroviruses. We chose X-linked chronic granulomatous disease (X-CGD) as model evaluate potential of self-inactivating (SIN) alpharetroviral vectors for gene therapy monogenic diseases. Therefore, we combined vector backbone with elongation factor-1α short promoter, both considered possess a low genotoxic profile, drive transgene (gp91phox) expression. Following...
Gene therapy for hematological disorders relies on the genetic modification of CD34+ cells, a heterogeneous cell population containing about 0.01% long-term repopulating cells. Here, we show that lentiviral vector CD133-LV, which uses surface marker human primitive hematopoietic stem cells (HSCs) as entry receptor, transfers genes preferentially into with high engraftment capability. Transduction unstimulated CD133-LV resulted in gene marking competitive proliferative advantage vitro and...
Ex vivo expansion of human CD34+ hematopoietic stem and progenitor cells remains a challenge due to rapid differentiation after detachment from the bone marrow niche. In this study, we assessed capacity an inducible fusion protein enable sustained ex proliferation precursors their differentiate into functional phagocytes. We fused coding sequences FK506-Binding Protein 12 (FKBP12)-derived destabilization domain (DD) myeloid/lymphoid lineage leukemia/eleven nineteen leukemia (MLL-ENL) gene...
Abstract ZBTB7A is frequently mutated in acute myeloid leukemia (AML) with t(8;21) translocation. However, the oncogenic collaboration between and RUNX1–RUNX1T1 fusion gene AML remains unclear. Here, we investigate role of its mutations context normal malignant hematopoiesis. We demonstrate that clinically relevant lead to loss function result perturbed differentiation block granulocytic lineage favor monocytic commitment. In addition, increases glycolysis hence sensitizes leukemic blasts...
Targeting transgene expression to specific hematopoietic cell lineages could contribute the safety of retroviral vectors in gene therapeutic applications. Chronic granulomatous disease (CGD), a defect phagocytic cells, can be managed by therapy, using with targeted myeloid cells. In this context, we analyzed myelospecificity human miR223 promoter, which is known strongly upregulated during differentiation, drive myeloid-restricted p47phox and gp91phox mouse models CGD primary patient-derived...
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As monogenic affecting the hematopoietic system, CGD amenable to gene therapy. Indeed phase I/II clinical trial, we demonstrated transient resolution of bacterial and fungal infections. However, therapeutic benefit was compromised occurrence clonal dominance malignant transformation demanding alternative vectors with equal efficacy but safety-improved...
Primary human blood cells represent an essential model system to study physiology and disease. However, is a limited resource. During healthy donor plateletpheresis, the leukoreduction chamber (LRSC) reduces leukocyte amount within subsequent platelet concentrate through saturated, fluidized, particle bed filtration technology. Normally, LRSC discarded after apheresis completed. Compared peripheral blood, yields 10-fold mononuclear cell concentration.
Activating colony-stimulating factor-3 receptor gene (CSF3R) mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations CSF3R and associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, blast-like morphology distinct immunophenotype. Gene profiling revealed...
GATA2 zinc-finger (ZF) mutations are associated with distinct entities of myeloid malignancies. The specific distribution these points toward different mechanisms leukemogenesis depending on the ZF domain affected. In this study, we compared recurring somatic in ZF1 and ZF2. All tested mutants disrupted DNA binding vitro. transcription assays, co-expression FOG1 counteracted GATA2-dependent transcriptional activation, while a variable response to FOG1-mediated repression was observed for...