Funktionella studier i multipelt myelom av kandidatgener för tumörens överlevnad i signalvägar för IGF-1R och i epigenetiskt reglerade gensignaturer - Implikationer för biologi och ny terapi
Tidsperiod: 2018-01-01 till 2021-12-31
Projektledare: Helena Jernberg Wiklund
Budget: 4 800 000 SEK
The overall objective of this proposal is to dissect a disease-specific global epigenetic pattern of clinical importance for multiple myeloma (MM), to increase understanding of how epigenetic abnormalities are important in development, drug resistance and stemness, and to evaluate the use of epigenetic modifiers as therapeutic targets. We have generated the first global analysis on the distribution of histone marks in MM and normal plasma cells and presented an initial proof-of-concept that silenced genes may be reactivated by use of epigenetic inhibitors. This proposal consists of three integrated projects. In the first we are systematically mapping the intrinsic network of epigenetic modifiers of histone i.e. Polycomb group (PcG), and of DNA collaborating to maintain gene silencing in MM. Epigenomic changes of pathogenetic and clinical importance in MM will be identified. In the second, components of PcG complexes and targets are functionally studied using knockdown by lentiviral vectors, CRISPR/Cas9 and selective small chemical inhibitors of clinical relevance in vitro and in vivo. Biological and therapeutical implications of reactivation of target genes, miRNAs and enhancer regions will be studied. The third project is focused on drug resistance mechanisms including analysis by masspectrometry the role of alternate usage of metabolic pathways, and strategies of combined targeting of epigenetic modifiers (PRC2, PRC1, DNMTs, MYC) to achieve proof of concept for use in vivo.