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    Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells

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    Issue Date
    2020-04-20
    Author
    Perry, John M.
    Tao, Fang
    Roy, Anuradha
    Lin, Tara
    He, Xi C.
    Chen, Shiyuan
    Lu, Xiuling
    Nemechek, Jacqelyn
    Ruan, Linhao
    Yu, Xiazhen
    Dukes, Debra
    Moran, Andrea
    Pace, Jennifer
    Schroeder, Kealan
    Zhao, Meng
    Venkatraman, Aparna
    Qian, Pengxu
    Li, Zhenrui
    Hembree, Mark
    Paulson, Ariel
    He, Zhiquan
    Xu, Dong
    Tran, Thanh-Huyen
    Deshmukh, Prashant
    Nguyen, Chi Thanh
    Kasi, Rajeswari M.
    Ryan, Robin
    Broward, Melinda
    Ding, Sheng
    Guest, Erin
    August, Keith
    Gamis, Alan S.
    Godwin, Andrew
    Sittampalam, G. Sitta
    Weir, Scott J.
    Li, Linheng
    Publisher
    Nature Research
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Copyright © 2020, The Author(s), under exclusive license to Springer Nature Limited.
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    Abstract
    Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-catenin and PI3K–Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.
    URI
    http://hdl.handle.net/1808/32489
    DOI
    https://doi.org/10.1038/s41556-020-0507-y
    Collections
    • High Throughput Screening Laboratory Scholarly Works [13]
    Citation
    Perry, J.M., Tao, F., Roy, A. et al. Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells. Nat Cell Biol 22, 689–700 (2020). https://doi.org/10.1038/s41556-020-0507-y

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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