For more information please contact Prof. dr. Zeger Debyser, tel.: +32 16 37 40 29, mail: email@example.com.You can apply for this job no later than May 20, 2021 via the online application tool
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The network of interactions between proteins and other molecules in a cell is called the interactome and determines the normal physiological functions of a cell or organism. Inborn or acquired malfunctioning of the interactome results in human disease (infectious diseases, cancer,…). The Laboratory for Molecular Virology and Gene Therapy focuses on major human health challenges like HIV infection and Leukemia. With an emphasis on interactome studies we try to identify new targets and small molecules to treat these diseases. In 2003 we identified the ‘Lens Epithelium Derived Growth Factor’ (LEDGF/p75) as an important cellular interaction partner of HIV integrase, targeting the viral DNA to the host cell chromatin. Today this interaction is considered as an important new antiviral target. Subsequently it was shown that LEDGF/p75 performs a similar function during the development of MLL rearranged Leukemia, a poor prognosis leukemia particularly prevalent in infants.Our interdisciplinary group bridges basic research with drug discovery.
We are looking for a highly motivated PhD student to perform cutting edge research in a highly dynamic team. The candidate will study the cellular function of LEDGF/p75, its function during the development of MLL rearranged leukemia and its value as new therapeutic target. The proposed project will combine biochemical, cellular, and molecular techniques as well as animal experiments.
Understanding the role ofLEDGF/p75 and HRP-2 expression in cell survival and chemoresistance.
Mixed lineage leukemia-rearranged (MLLr) leukemia is a genetically distinct subtype of leukemia driven by a reciprocal chromosomal translocation or partial tandem duplications of internal coding regions of the MLL1 gene KMT2A. These rearrangements result in in-frame genes, translated to oncogenic fusion proteins deregulating the MLL1 target genes (e.g. HoxA family, Meis1, Cdk6), promoting leukemogenesis and tumor progression. Approximately 10% of leukemia patients worldwide are affected by MLL1 rearrangements, the majority of them are pediatric patients (less than 1 year old) affected by ALL, and young to middle age patients affected by AML. Overall, patients with MLL1 rearrangements are linked to a poor prognosis with a restricted 5 years survival mainly due to tumor recurrence and the lack of specific treatments. Therefore, there is an urgent need of developing novel, more specific therapies against MLL.
As a histone methyltransferase, MLL1 drives gene expression and is essential for body plan formation and normal hematopoiesis. The N-terminus of MLL1 forms a triple complex with MENIN and LEDGF/p75. LEDGF/p75 targets the MLL1 complex to its target genes and MENIN serves as an adaptor stabilizing the MLL1-LEDGF/p75 interaction. After the initial description of the role of LEDGF/p75 as a tether for MLL1r in MLL, we studied in detail the disease driving mechanism of LEDGF/p75 in MLL1r-induced leukemia and demonstrated that LEDGF/p75 is essential for leukemic transformation in mice, yet is dispensable for normal hematopoiesis. In addition, competitive overexpression of the IBD domain that can bind MLL1 but not chromatin, dramatically reduced clonogenic growth and MLL1 target gene expression in primary murine hematopoietic stem cells, in human cell lines immortalized by MLL1 fusion proteins and in a mouse model. These data corroborate the importance of LEDGF/p75 for MLL1-rearranged transformation and pinpoint the MLL1r-LEDGF/p75 interaction as a valid target for MLL.
Hepatoma derived growth factor related protein 2 (HRP-2/HDGF2) is the only human paralogue of LEDGF/p75 with identical functional domains. We are studying the role of HRP-2 in the development of MLLr leukemia. HRP-2interacts with MLL1 in a MENIN-independent way. Although, HRP-2 appears to be dispensable for the initiation of MLLr leukemia, HRP-2 may have a more general role in the survival of leukemic cells. Next to the main tethering role of LEDGF/p75 and HRP-2, high LEDGF/p75 levels have recently been associated with drug resistance in prostate and breast cancer. Yet, the mechanism remains unclear.
In this PhD project the candidate will investigate the underlying regulatory mechanism for this drug resistance induced by the LEDGF/p75 overexpression. This research can lead to novel therapeutic strategies against MLL, leukemia and other cancers.
Sharma, S., Cermakova, K., De Rijck, J., Demeulemeester, J., Fabry, M., El Ashkar, S., Van Belle, S., Lepsik,M., Tesina, P., Duchoslav, V., Novak, P., Hubalek, M., Srb, P., Christ, F.,Rezacova, P., Hodges, H.C., Debyser, Z., Veverka, V. (2018). Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation. Proceedings of the National Academy of Sciences f the United States of America, 115 (30), E7053-E7062.
Elashkar,S., Schwaller, J., Pieters, T., Goossens, S., Demeulemeester, J., Christ, F.,Van Belle, S., Juge, S., Boeckx, N., Engelman, A., Van Vlierberghe, P., Debyser, Z., De Rijck, J. (2017). LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis. Blood, 131 (1), 95-107.
A full time PhD position within an internationally leading multidisciplinary team with relevant experience and expertise. For this job, a contract of 1 year is offered that, after a positive evaluation, can be extended up to 4 years.Requirement to apply to competitive fellowships.