WEHI PhD Completion Seminar hosted by Professor Marco Herold

Gaoyuan Wang

PhD Student – Herold & Strasser Laboratories, Blood Cells & Blood Cancer division, WEHI

Developing advanced CRISPR technologies to study therapy resistance in haematopoietic malignancies

 

Davis Auditorium

Join via SLIDO enter code #WEHIphdcompletion

Including Q&A session

Followed by refreshments in Tapestry Lounge

Venetoclax is a BCL-2-specific BH3-mimetic drug that is FDA approved for the treatment of Chronic Lymphocytic Leukemia (CLL) and Acute Myeloid Leukemia (AML). While initial treatment success was very high, recent reports suggest relapse of patients being treated with venetoclax. Hence, identifying resistance factors to venetoclax therapy is an area of great clinical relevance. We are interested in developing advanced CRISPR technologies to address this issue and explore resistance at the single cell level. We designed a CRISPR droplet sequencing (CROP-seq) based transcriptional activation library to upregulate genes that mimic signals from the microenvironment which may contribute to resistance. The CROP-seq method allows detection of each cell’s sgRNA along with its single cell transcriptomic landscape, providing gene expression signatures for individual gene perturbations. In our in vitro study, we showed that CROPseq activation screening system works effectively to identify clinically known and novel resistance factors for venetoclax treatment. We then took this research to the next level, combining CROPseq activation screening with another advanced technique, spatial transcriptomics, to enable us to investigate the impact of the tumour microenvironment on the response of cancer cells to venetoclax treatment in vivo. We showed that high expression of target genes could potentially be used as a signature to correlate CROPseq and spatial transcriptomic datasets and identified several potential hits from in vivo CRISPR activation screening.

All welcome!