Targeting c-MYB in Acute Leukaemia through Drug Repositioning

Novel treatments are urgently needed for childhood acute myeloid leukaemia (AML). The transcription factor c-MYB plays a central role in the development and maintenance of AML. We hypothesised that deregulation of c-MYB could be a therapeutic approach. We identified Withferin A (WfA) as a candidate for such therapy using connectivity MAP analysis. WfA induced degradation of c-MYB in AML cell lines, and demonstrated anti-leukaemic properties in vitro, inducing apoptosis and increased expression of differentiation antigens, and inhibiting colony formation. We provide initial evidence that a major part of WFA activity is through inhibition of oncogenic activation of c-MYB target genes: enrichment of a c-MYB activated gene list in drug-induced gene expression changes; partial rescue of colony formation and protein degradation in response to transient exposure to WFA, following expression of degradation-resistant c-MYB in AML cells. This work will now be extended to explore the mechanism by which WFA is modulating c-MYB, and its efficacy in primary patient-derived cells in vitro and in vivo.