Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival
Yaoyu Chen, … , Tessa L. Holyoake, Shaoguang Li
Yaoyu Chen, … , Tessa L. Holyoake, Shaoguang Li
Published August 8, 2014
Citation Information: J Clin Invest. 2014;124(9):3847-3862. https://doi.org/10.1172/JCI66129.
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Research Article Oncology

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

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.

Authors

Yaoyu Chen, Cong Peng, Sheela A. Abraham, Yi Shan, Zhiru Guo, Ngoc Desouza, Giulia Cheloni, Dongguang Li, Tessa L. Holyoake, Shaoguang Li

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Figure 10

Inhibition of Alox15 function suppresses primary human CML cells.

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Inhibition of Alox15 function suppresses primary human CML cells. (A) CM...
(A) CML CD34+ cells were treated with PD146176 for 24 or 72 hours. Cells were counted using the trypan blue exclusion assay (top), and apoptosis was assessed (annexin V+7AAD+) by FACS (bottom). (B) CML CD34+ cells were treated with PD146176, imatinib, or nilotinib alone or in combination for 24 hours (top) or 72 hours (bottom). The percentage of viable and apoptotic (annexin V+7AAD+) cells was analyzed. Results represent the mean ± SEM. (C) CML or normal CD34+ cells were treated with PD146176, imatinib, or nilotinib alone or in combination for 24 hours (top) or 72 hours (bottom) and replated for the CFC assay. Results represent the mean ± SEM. *P < 0.05.