Kurzfassung

The role of epigenetic abnormalities (DNMT3A, TET1/2…) as drivers of tumorigenesis has been increasingly recognized in recent years, especially in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These epigenetic alterations are accompanied by hundreds of genes known to be differentially silenced in association with DNA hypermethylation of CpG islands in promoter regions. A key group of these specific loci are known to function as tumor suppressor genes (TSG). Targeted...The role of epigenetic abnormalities (DNMT3A, TET1/2…) as drivers of tumorigenesis has been increasingly recognized in recent years, especially in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These epigenetic alterations are accompanied by hundreds of genes known to be differentially silenced in association with DNA hypermethylation of CpG islands in promoter regions. A key group of these specific loci are known to function as tumor suppressor genes (TSG). Targeted reversal of gene silencing by epigenetic drugs (like DNA methyltransferase inhibitors) is an attractive strategy for cancer prevention and therapy but currently remains limited in MDS/AML due to the lack of reliable TSG biomarkers and poor pharmacodynamics and -kinetics of current FDA/EMA-approved hypomethylating compounds. More importantly, recent findings demonstrate that epigenetic therapy can induce an innate immune activation in MDS/AML cells which might prime cancer cells for an immune response, highlighting the potential to combine epigenetic therapy with immunotherapy.
By using in silico and preclinical analysis approach based on DNA methylation/gene expression data sets, our lab aims to identify potential biomarkers or targets that are highly silenced across different MDS and AML mutational landscapes. We will analyze the re-expression of these gene candidates and assess their potential as therapeutic targets or modulators of metabolic and/or immune response.  Similarly, we are also developing novel reporter MDS/AML cell lines using Crispr/Cas9 technology to help understand the contribution of these silenced genes in drug resistance. Furthermore, these cell lines will be used in functional and drug screening assays to develop novel epigenetic regimens that may be broadly applicable to enhance the efficacy of current radiotherapy, chemotherapy or immunotherapy therapies.» weiterlesen» einklappen