Developing a Y-chromosome targeted therapeutic for lymphomas bearing mutations of X-encoded tumour suppressors

Lymphomas bearing translocations of the MYC oncogene represent some of the most aggressive blood cancers in the clinic - Burkitt lymphoma and Diffuse Large B-cell Lymphoma. MYC driven lymphomas are enriched for mutations in an X-encoded tumour suppressor gene called DDX3X. DDX3X is an RNA helicase that performs many important roles in RNA metabolism and protein synthesis. Despite functioning as an X-linked tumour suppressor, DDX3X function is essential for cell survival. Thus, female lymphomas with a DDX3X mutation 'unsilence' their second DDX3X allele to survive. Male lymphomas cannot do this and instead must re-express the Y-chromosome encoded paralogue, DDX3Y in order to survive. As DDX3Y is not normally expressed outside of the testis, the male DDX3X mutated lymphoma cells are uniquely reliant on DDX3Y for viability. Our project seeks to exploit this 'synthetic lethality' to develop a new precision targeted therapy for aggressive lymphoma. Using sophisticated technologies including high-throughput drug screens, CRISPR/Cas9 genomic screening, lipid-nanoparticle based mRNA delivery systems and degron-tagged cell lines we will decipher mechanisms of DDX3Y regulation and DDX3Y inhibitors for therapeutic evaluation.