Identification of a c-MYB-directed therapeutic for acute myeloid leukemia

A significant proportion of patients who have acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, with relapsed disease being a common problem. Molecular targeting of essential oncogenic mediators is an attractive approach to improving outcomes for this disease. The hematopoietic transcription factor c-MYB has been a central component of complexes maintaining aberrant gene expression programs in AML. The study have previously screened the Connectivity Map database to identify mebendazole as an anti-AML therapeutic targeting c-MYB. The study aimed to demonstrate that another hit from this screen, the steroidal lactone withaferin A (WFA), induces rapid ablation of c-MYB protein and consequent inhibition of c-MYB target gene expression, loss of leukemia cell viability, reduced colony formation and impaired disease progression. Although WFA has been reported to have pleiotropic anti-cancer effects, the study demonstrates that its anti-AML activity depends on c-MYB modulation and can be partially reversed by a stabilized c-MYB mutant. c-MYB ablation results from disrupted HSP/HSC70 chaperone protein homeostasis in leukemia cells following induction of proteotoxicity and the unfolded protein response by WFA. The widespread use of WFA in traditional medicines worldwide indicates that it represents a promising candidate for repurposing into AML therapy.