Genetics; Leukemia; Receptors, Notch; Therapeutics
- Comprehensive Cancer Center Vienna / Drug & Target Screening Unit
The main focus of our research is elucidating the initiation/clonal evolution/maintenance of neoplastic cells with special emphasis on the NOTCH2 signaling network in chronic lymphocytic leukemia (CLL). The cancer initiating oncogene NOTCH2 is frequently deregulated in leukemias/solid tumors, making NOTCH2 an ideal target for therapeutic interventions. We have recently shown that the Aspergillus derived secondary metabolite gliotoxin is a potent nuclear NOTCH2 inhibitor and efficiently targets neoplastic cells in vitro and in a melanoma xenotransplant mouse model in vivo.
Our preliminary data indicates, that the NOTCH2 gain of function (GOF) phenotype in CLL cells is induced by intragenic somatic recombination between two inherited non-compatible NOTCH2 haplotypes. We focus on screening whole genome/exome sequencing data (WGS/WES) for new singel nucleotide variation (SNV) combinations that lead to the loss of the NOTCH2 negative regulatory region (NRR) by aberrant splicing. This will include geographical and gender aspects. The most frequent NOTCH2 SNV combinations will be the basis for the development of RFLP assays as predictive/diagnostic tool for NOTCH2 associated malignancies.
Techniques, methods & infrastructure
Cocultur models to mimic the CLL Tumor microenvironment for drug screening assays. FACS, RT-PCR, EMSA, Western bloting, WGS/WES sequence analysis, gene silencing for functional studies, RFLP, diagnostic tool development.
- Hubmann, R. et al., 2012. Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells. Br J Haematol, 160(5), pp.618-629. Available at: http://dx.doi.org/10.1111/bjh.12183.
- Hubmann, R. et al., 2010. NOTCH2 links protein kinase C delta to the expression of CD23 in chronic lymphocytic leukaemia (CLL) cells. British Journal of Haematology, 148(6), pp.868-878. Available at: http://dx.doi.org/10.1111/j.1365-2141.2009.08024.x.
- Duechler, M. et al., 2004. Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2. Leukemia, 19(2), pp.260-267. Available at: http://dx.doi.org/10.1038/sj.leu.2403592.
- Hubmann, R. et al., 2002. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood. 2002 May 15;99(10):3742-7.
- Hubmann, R. et al., 2017. Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model. Frontiers in Pharmacology, 8. Available at: http://dx.doi.org/10.3389/fphar.2017.00319.