Pharmacological or genetic inhibition of hypoxia signaling attenuates oncogenic RAS-induced cancer phenotypes.
Drosophila
Echinomycin
HIF1A
Hypoxia pathway
Leukemia
Mouse xenografts
Oncogenic RAS
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
01 02 2022
01 02 2022
Historique:
received:
03
02
2021
accepted:
18
09
2021
pubmed:
29
9
2021
medline:
1
4
2022
entrez:
28
9
2021
Statut:
ppublish
Résumé
Oncogenic Ras mutations are highly prevalent in hematopoietic malignancies. However, it is difficult to directly target oncogenic RAS proteins for therapeutic intervention. We have developed a Drosophila acute myeloid leukemia model induced by human KRASG12V, which exhibits a dramatic increase in myeloid-like leukemia cells. We performed both genetic and drug screens using this model. The genetic screen identified 24 candidate genes able to attenuate the oncogenic RAS-induced phenotype, including two key hypoxia pathway genes HIF1A and ARNT (HIF1B). The drug screen revealed that echinomycin, an inhibitor of HIF1A, can effectively attenuate the leukemia phenotype caused by KRASG12V. Furthermore, we showed that echinomycin treatment can effectively suppress oncogenic RAS-driven leukemia cell proliferation, using both human leukemia cell lines and a mouse xenograft model. These data suggest that inhibiting the hypoxia pathway could be an effective treatment approach and that echinomycin is a promising targeted drug to attenuate oncogenic RAS-induced cancer phenotypes. This article has an associated First Person interview with the first author of the paper.
Identifiants
pubmed: 34580712
pii: 272327
doi: 10.1242/dmm.048953
pmc: PMC8617310
pii:
doi:
Substances chimiques
Echinomycin
512-64-1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI064350
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK098410
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134940
Pays : United States
Informations de copyright
© 2021. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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