Department of Medicine, Division of Hematology Oncology
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
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.
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DOI of Published Version
J Clin Invest. 2014 Sep;124(9):3847-62. doi: 10.1172/JCI66129. Epub 2014 Aug 8. Link to article on publisher's site
The Journal of clinical investigation
Chen Y, Peng C, Abraham SA, Shan Y, Guo Z, Desouza N, Cheloni G, Li D, Holyoake TL, Li S. (2014). Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival. Hematology Oncology Publications. https://doi.org/10.1172/JCI66129. Retrieved from https://escholarship.umassmed.edu/hema_oncology_pubs/1