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    Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival

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    Authors
    Chen, Yaoyu
    Peng, Cong
    Abraham, Sheela A.
    Shan, Yi
    Guo, Zhiru
    Desouza, Ngoc
    Cheloni, Giulia
    Li, Dongguang
    Holyoake, Tessa L.
    Li, Shaoguang
    UMass Chan Affiliations
    Department of Medicine, Division of Hematology Oncology
    Document Type
    Journal Article
    Publication Date
    2014-09-01
    Keywords
    Animals
    Apoptosis
    Arachidonate 15-Lipoxygenase
    Cell Line, Tumor
    Cells, Cultured
    Fluorenes
    Fusion Proteins, bcr-abl
    Humans
    Leukemia, Myelogenous, Chronic, BCR-ABL Positive
    Lipoxygenase Inhibitors
    Mice
    Mice, Inbred C57BL
    Neoplastic Stem Cells
    P-Selectin
    Cancer Biology
    Hematology
    Hemic and Lymphatic Diseases
    Neoplasms
    Oncology
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    Abstract
    Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML.
    Source
    J Clin Invest. 2014 Sep;124(9):3847-62. doi: 10.1172/JCI66129. Epub 2014 Aug 8. Link to article on publisher's site
    DOI
    10.1172/JCI66129
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/34788
    PubMed ID
    25105362
    Related Resources
    Link to Article in PubMed
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    Publisher PDF posted as allowed by the publisher's author rights policy at http://content-assets.jci.org/admin/forms/jcicopyright.pdf.

    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI66129
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