Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival
Yaoyu Chen, Cong Peng, Sheela A. Abraham, Yi Shan, Zhiru Guo, Ngoc Desouza, Giulia Cheloni, Dongguang Li, Tessa L. Holyoake, Shaoguang Li
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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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 7

Loss of Alox15 depletes LSCs through its downstream gene Selp.

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Loss of Alox15 depletes LSCs through its downstream gene Selp. (A) Gene ...
(A) Gene expression profiles of WT and Alox15–/– HSCs were compared by DNA microarray analysis. In the absence of Alox15, the Selp gene was upregulated. (B) FACS analysis showed that Selp expression on the cell surface was upregulated by treating K562 cells with PD146176. (C) FACS analysis showed that Selp expression on K562 cells was downregulated after treatment with 15S-HETE or lipoxinA4 for 48 hours. (D) Rescue of the defective CML phenotype by the deletion of Selp in Alox15–/– BM cells. Alox15–/– mice were crossed with Selp–/– mice to generate Alox15–/–Selp–/– homozygous double-knockout mice. Kaplan-Meier survival curves for recipients of BCR-ABL–transduced BM cells from WT, Selp–/–, Alox15–/–, and Selp–/– Alox15–/– donor mice. (E) Rescue of the defective CML phenotype by the deletion of Selp in Alox15–/– BM cells correlated with a high number of LSCs in BM. On day 14 after CML induction, LSCs in recipients of BCR-ABL–transduced BM cells from WT, Selp–/–, Alox15–/–, and Selp–/– Alox15–/– donor mice were determined by FACS. Results represent the mean ± SD. (F) Rescue of the defective CML phenotype by deletion of Selp in Alox15–/– BM cells correlated with a high number of leukemia cells (GFP+Gr-1+) in the PB of recipients of BCR-ABL–transduced BM cells from WT, Selp–/–, Alox15–/–, and Selp–/– Alox15–/– donor mice. Results represent the mean ± SD. (G) Photomicrographs of H&E-stained lung sections from recipients of BCR-ABL–transduced BM cells from WT, Selp–/–, Alox15–/–, and Selp–/– Alox15–/– donor mice. *P < 0.05; **P < 0.01.