Lay summary
It is rare to identify completely new genetic pathways that lead to cancer. However, the incentive to do so remains strong, to identify novel opportunities for therapeutics. Recent whole genome sequencing approaches have pinpointed mutations in genes that were previously not associated with cancer. For acute myeloid leukaemia (AML) this approach revealed that 9-13% have mutations in genes encoding the chromosome cohesion complex, cohesin. Cohesin mutations represent a new genetic pathway for AML, but how AML arises from these mutations is unknown. We found that cohesin regulates expression of a gene already well known to cause AML: RUNX1. We hypothesise that cohesin mutations cause AML by leading to abnormal RUNX1 expression. First, we will test this hypothesis using multiple molecular approaches in leukaemia cells and a zebrafish in vivo model. Second, we will screen for drugs that selectively target cohesin-mutant leukaemias, and characterise their activity in human cells and zebrafish.