Developing novel therapeutics to target splicing factor mutant myeloid malignancies

Project Outline

Aberrant splicing is a pervasive, driving pathological feature of several blood cancers, as evidenced by the high frequency of mutations involving splicing machinery components, which range from 20% to 70% depending on the specific blood cancer type. Leukaemia patients with splicing factor mutations generally have worse overall survival than those with splicing factor-wild type, highlighting the need for better treatment strategies for this group of patients. Moreover, given the diverse downstream transcriptional consequences of these mutations, there is strong premise that cryptic novel therapeutic vulnerabilities might be exposed.

To identify novel candidate therapeutic targets for splicing factor-mutant blood cancers, we have performed CRISPR-KO synthetic lethality screens in isogenic myeloid leukaemia cell lines that mimic the most frequently observed splicing factor mutations (N=5). This approach allowed us to identify several targets whose loss uniquely induced cell death in one or more mutant lines, but not in wild type leukaemia cells. By seeking common vulnerabilities, we have identified synthetic lethal hits shared by at least three of the mutant lines. A functional enrichment analysis of these hits revealed that most hits are associated with three important cellular pathways.

The prospective student will validate these findings, investigate the mechanisms underlying the observed instances of synthetic lethalities, and assess the therapeutic effectiveness of targeting these pathways in splicing factor-mutant cell lines, primary patient samples, and animal models. The identification of novel therapeutics that target multiple splicing factor mutations (representing a significant proportion of leukaemia patients overall) holds immense significance and will pave a clear path towards clinical trials. The approach – agnostic to disease category and rather focusing on shared biology – represents a different paradigm that could extend applicability of outputs (and impact) across a wide range of disease areas.

Applications for this project are now open. Please complete your application on The University of Manchester website.