Projects
Novel HIV inhibitors targeting the interaction between integrase and LEDGF/p75 KU Leuven
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A novel therapeutic approach for acute leukemia by targeting LEDGF/p75. KU Leuven
Mixed-lineage leukemias (MLL) represent a genetically distinct subset of acute leukemias characterized by chromosomal translocations in the MLL gene. Balanced rearrangements result in the formation of new fusion proteins inducing myeloid as well as lymphoblastic leukemias with poor prognosis. All N-terminal MLL fusions (MLLNT-fusions) form a complex with the lens epithelium-derived growth factor (LEDGF/p75) and MENIN. LEDGF/p75, a chromatin ...
LEDGF/p75 chromatin tethering as a target to treat Jpo2 and MLL dependent malignancies KU Leuven
When all links between genes associated with disease development (diseaseome) and virushost interactions (infectome) are mapped, a network emerges revealing common genetic origin of many diseases and viral infections. In addition, interaction nodes or protein hubs appear with a central function in many disorders or infections. In the proposed project we study ‘Lens Epithelium Derived Growth Factor/p75’ (LEDGF/p75), originally discovered in ...
LEDGINs and the molecular mechanism of LEDGF/p75 mediated HIV integration. KU Leuven
Targeted editing of the PSIP1 gene encoding LEDGF/p75 protects cells against HIV infection KU Leuven
Gene therapy has long held promise to correct a variety of human diseases. Discovery of the Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR), the mechanism of the CRISPR-based prokaryotic adaptive immune system (CRISPR-associated system, Cas) and its repurposing into a potent gene editing tool has revolutionized the field of molecular biology and generated excitement for new and improved gene therapies. Additionally, the ...
Design of targeted degraders of LEDGF/p75 with applications as anticancer agents KU Leuven
LEDGF/p75 is a protein that plays a major role in transcriptional activation and tethers epigenetic regulators such as KMT2A to the chromatin, enabling transcription. C-terminal KMT2A-rearranged proteins maintain interactions with LEDGF/p75, leading to aberrant transcription. This plays a particularly important role in leukemogenesis leading to mixed lineage forms of leukemia, with very poor survival rates with infant patient populations. In ...
Development of an LEDGF/p75 based strategy for the treatment of MLL-rearranged leukemia. KU Leuven
MLL-rearranged (MLL-r) acute leukemias represent a genetically distinct subset of leukemia originating from rearrangements in the MLL (Mixed lineage leukemia) gene. MLL-r leukemia is especially prevalent in infants (0-1y) and compared to most types of leukemia, patients face an adverse clinical outcome (15-40 % event-free survival at 48 months). New treatment strategies are urgently needed since no specific treatment for these patients is ...
Role of the epigenetic reader LEDGF/p75 in health and disease KU Leuven
Structure-based design of inhibitors targeting the chromatin-reading function of LEDGF/p75 to treat acute mixed-lineage leukemia KU Leuven
Mixed-lineage leukemia rearranged (MLL-r) is an acute leukemia mostly affecting children and associated with poor survival. The disease is caused by rearrangements in the MLL gene resulting in malignant fusion proteins. LEDGF/p75 serves as an epigenetic reader and tethers transcription complexes containing MLL to chromatin via its PWWP domain. Recent studies demonstrated that this process is essential for the onset of MLL-r leukemia, yet it ...