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

Chen, Y., Peng, C., Abraham, S. A., Shan, Y., Guo, Z., Desouza, N., Cheloni, G., Li, D., Holyoake, T. L. and Li, S. (2014) Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival. Journal of Clinical Investigation, 124(9), pp. 3847-3862. (doi:10.1172/JCI66129) (PMID:25105362) (PMCID:PMC4151200)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Abraham, Dr Sheela
Authors: Chen, Y., Peng, C., Abraham, S. A., Shan, Y., Guo, Z., Desouza, N., Cheloni, G., Li, D., Holyoake, T. L., and Li, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Clinical Investigation
Publisher:Americal Society for Clinical Investigation
ISSN:0021-9738
ISSN (Online):1558-8238
Copyright Holders:Copyright © 2014 Americal Society for Clinical Investigation
First Published:First published in Journal of Clinical Investigation 124(9):3847-3862
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES
494701A phosphoproteomic investigation of key BCR-ABL mediated signally pathways in CML stem cells: where does tyrosine kinase inhibitor resistance lie?Tessa HolyoakeLeukaemia & Lymphoma Research (LRF)08071RI CANCER SCIENCES
634291Dual targeting of p53 and c-myc to eradicate CML stem cellsTessa HolyoakeLeukaemia & Lymphoma Research (LLR)13035ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
498551Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES
498552Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES