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    Pharmacological or genetic inhibition of hypoxia signaling attenuates oncogenic RAS-induced cancer phenotypes

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    Author
    Zhu, Jun-Yi
    Huang, Xiaohu
    Fu, Yulong
    Wang, Yin
    Zheng, Pan
    Liu, Yang
    Han, Zhe
    Date
    2021-09-28
    Journal
    Disease Models & Mechanisms
    Publisher
    Company of Biologists Ltd.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1242/dmm.048953
    Abstract
    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 (AML) 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 echinomycin, an inhibitor of HIF1A, could effectively attenuate the leukemia phenotype caused by KRASG12V. Furthermore, we showed that echinomycin treatment could 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 for oncogenic RAS-induced cancer phenotype, and that echinomycin is a promising targeted drug to attenuate oncogenic RAS-induced cancer phenotypes.
    Rights/Terms
    © 2021. Published by The Company of Biologists Ltd.
    Keyword
    Drosophila
    Echinomycin
    HIF1A
    Hypoxia pathway
    Leukemia
    Mouse xenografts
    Oncogenic RAS
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16755
    ae974a485f413a2113503eed53cd6c53
    10.1242/dmm.048953
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