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dc.contributor.authorPerry, John M.
dc.contributor.authorTao, Fang
dc.contributor.authorRoy, Anuradha
dc.contributor.authorLin, Tara
dc.contributor.authorHe, Xi C.
dc.contributor.authorChen, Shiyuan
dc.contributor.authorLu, Xiuling
dc.contributor.authorNemechek, Jacqelyn
dc.contributor.authorRuan, Linhao
dc.contributor.authorYu, Xiazhen
dc.contributor.authorDukes, Debra
dc.contributor.authorMoran, Andrea
dc.contributor.authorPace, Jennifer
dc.contributor.authorSchroeder, Kealan
dc.contributor.authorZhao, Meng
dc.contributor.authorVenkatraman, Aparna
dc.contributor.authorQian, Pengxu
dc.contributor.authorLi, Zhenrui
dc.contributor.authorHembree, Mark
dc.contributor.authorPaulson, Ariel
dc.contributor.authorHe, Zhiquan
dc.contributor.authorXu, Dong
dc.contributor.authorTran, Thanh-Huyen
dc.contributor.authorDeshmukh, Prashant
dc.contributor.authorNguyen, Chi Thanh
dc.contributor.authorKasi, Rajeswari M.
dc.contributor.authorRyan, Robin
dc.contributor.authorBroward, Melinda
dc.contributor.authorDing, Sheng
dc.contributor.authorGuest, Erin
dc.contributor.authorAugust, Keith
dc.contributor.authorGamis, Alan S.
dc.contributor.authorGodwin, Andrew
dc.contributor.authorSittampalam, G. Sitta
dc.contributor.authorWeir, Scott J.
dc.contributor.authorLi, Linheng
dc.date.accessioned2022-02-04T14:54:07Z
dc.date.available2022-02-04T14:54:07Z
dc.date.issued2020-04-20
dc.identifier.citationPerry, 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-yen_US
dc.identifier.urihttp://hdl.handle.net/1808/32489
dc.description.abstractLeukaemia 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.en_US
dc.publisherNature Researchen_US
dc.rightsCopyright © 2020, The Author(s), under exclusive license to Springer Nature Limited.en_US
dc.subjectCancer immunotherapyen_US
dc.subjectCancer stem cellsen_US
dc.subjectCancer therapeutic resistanceen_US
dc.subjectCell signalingen_US
dc.titleOvercoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cellsen_US
dc.typeArticleen_US
kusw.kuauthorRoy, Anuradha
kusw.kudepartmentHigh Throughput Screening Laboratoryen_US
dc.identifier.doi10.1038/s41556-020-0507-yen_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC8010717en_US
dc.rights.accessrightsopenAccessen_US


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