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dc.contributor.authorChen, Yaoyu
dc.contributor.authorPeng, Cong
dc.contributor.authorAbraham, Sheela A.
dc.contributor.authorShan, Yi
dc.contributor.authorGuo, Zhiru
dc.contributor.authorDesouza, Ngoc
dc.contributor.authorCheloni, Giulia
dc.contributor.authorLi, Dongguang
dc.contributor.authorHolyoake, Tessa L.
dc.contributor.authorLi, Shaoguang
dc.date2022-08-11T08:09:07.000
dc.date.accessioned2022-08-23T16:18:19Z
dc.date.available2022-08-23T16:18:19Z
dc.date.issued2014-09-01
dc.date.submitted2016-04-29
dc.identifier.citationJ Clin Invest. 2014 Sep;124(9):3847-62. doi: 10.1172/JCI66129. Epub 2014 Aug 8. <a href="http://dx.doi.org/10.1172/JCI66129">Link to article on publisher's site</a>
dc.identifier.issn0021-9738 (Linking)
dc.identifier.doi10.1172/JCI66129
dc.identifier.pmid25105362
dc.identifier.urihttp://hdl.handle.net/20.500.14038/34788
dc.description.abstractCancer 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=25105362&dopt=Abstract">Link to Article in PubMed</a>
dc.rights<p>Publisher PDF posted as allowed by the publisher's author rights policy at http://content-assets.jci.org/admin/forms/jcicopyright.pdf.</p>
dc.subjectAnimals
dc.subjectApoptosis
dc.subjectArachidonate 15-Lipoxygenase
dc.subjectCell Line, Tumor
dc.subjectCells, Cultured
dc.subjectFluorenes
dc.subjectFusion Proteins, bcr-abl
dc.subjectHumans
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjectLipoxygenase Inhibitors
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectNeoplastic Stem Cells
dc.subjectP-Selectin
dc.subjectCancer Biology
dc.subjectHematology
dc.subjectHemic and Lymphatic Diseases
dc.subjectNeoplasms
dc.subjectOncology
dc.titleArachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival
dc.typeJournal Article
dc.source.journaltitleThe Journal of clinical investigation
dc.source.volume124
dc.source.issue9
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1000&amp;context=hema_oncology_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/hema_oncology_pubs/1
dc.identifier.contextkey8539233
refterms.dateFOA2022-08-23T16:18:20Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathhema_oncology_pubs/1
dc.contributor.departmentDepartment of Medicine, Division of Hematology Oncology
dc.source.pages3847-62


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