Identification of a c-MYB-directed therapeutic for acute myeloid leukemia.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
26
11
2021
accepted:
21
03
2022
revised:
07
03
2022
pubmed:
4
4
2022
medline:
7
6
2022
entrez:
3
4
2022
Statut:
ppublish
Résumé
A significant proportion of patients suffering from acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, 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 revealed as a central component of complexes maintaining aberrant gene expression programs in AML. We have previously screened the Connectivity Map database to identify mebendazole as an anti-AML therapeutic targeting c-MYB. In the present study we 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, we demonstrate 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 throughout the world indicates that it represents a promising candidate for repurposing into AML therapy.
Identifiants
pubmed: 35368048
doi: 10.1038/s41375-022-01554-9
pii: 10.1038/s41375-022-01554-9
pmc: PMC9162920
mid: EMS143962
doi:
Substances chimiques
Proto-Oncogene Proteins c-myb
0
Transcription Factors
0
Mebendazole
81G6I5V05I
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1541-1549Subventions
Organisme : Medical Research Council
ID : MR/S021000/1
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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