2013 - 2021
Identification and Evaluation of Candidate Drug Targets in CML Blast Crisis and secondary AML using regulatable in vivo RNAi.
The project part leader, Johannes Zuber, is group leader at the IMP, and well known in the scientific community. He established genetically modified mouse models in myeloid leukemias and suitable in vivo RNAi technologies focusing on the identification of new therapeutic targets in myeloid neoplasms. Based on this approach, the PI has recently identified BRD4 as a major drug target in AML.
The major aims in project #10 are to establish genetically and biologically defined “Tet-on competent” models of sAML and CML BC, to conduct pooled shRNA screening by using focused miR30-based RNAi libraries, to evaluate candidate drug targets using mosaic sAML/BC mouse models combined with transgenic RNAi, and to establish a Tet-on regulatable miR30-shRNA system for target evaluation in patient samples. The long term goal in project #10 is to identify new valuable therapeutic targets in advanced MPN, and to develop new treatment strategies employing these targets as well as various targeted drugs.
Project #10 contributes substantially to the common goal of this SFB for several reasons:During the first funding period, project #10 has become an integral member of the SFB consortium. Based on our expertise in the development and use of genetically engineered mouse models and functional-genetic approaches for the identification, validation and study of candidate therapeutic targets, project #10 contributes cutting-edge resources and know-how to the SFB program. These include genetically engineered Tet-on competent and Cas9-expressing sAML/BC models optimized for multiplexed screening and the validation of candidate targets in vitro and in vivo, the design and construction of customized shRNAmir/sgRNA vectors and libraries, multi¬plexed screening methods, and Tet-shRNAmir transgenic mice. During the first funding period, miR-E-based shRNA and CRISPR reagents and related know-how have been adapted by several SFB groups (e.g. #04, #06, #07, #11) and are now routinely used as standard tools for the validation and functional analysis of candidate targets. For mechanistic follow-up studies, we have recently established cutting-edge enhancer profiling (STARR-seq) and nascent mRNA-seq (SLAM-seq) technologies, which will be applied in several SFB collabo¬ra¬ti¬ons (e.g. with projects #04, #06, #07).