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 1

Alox15 is essential for CML induction by BCR-ABL.

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Alox15 is essential for CML induction by BCR-ABL. (A) DNA microarray ana...
(A) DNA microarray analysis showed upregulation of Alox15 expression by BCR-ABL in LSCs compared with GFP+Lin–Sca-1+c-Kit+ cells, which only expressed GFP, and this upregulation was not inhibited by imatinib. Results represent the mean ± SD (*P < 0.05). (B) RT-PCR confirmed the upregulation of Alox15 expression by BCR-ABL in LSCs in the presence and absence of imatinib treatment (*P < 0.05). Results represent the mean ± SD. (C) Kaplan-Meier survival curves for recipients of BCR-ABL–transduced BM cells from WT or Alox15–/– mice (8 mice per group). (D) Left: Gross appearance of CML mice, lung, and spleen of recipients of BCR-ABL–transduced BM cells from WT and Alox15–/– donor mice. Right: Photomicrographs of H&E-stained lung and spleen sections from recipients of BCR-ABL–transduced BM cells from WT or Alox15–/– donor mice. Original magnification, ×10 (top), ×40 (bottom). (E) In the absence of Alox15, the percentage of GFP+Gr-1+ cells in PB started to decrease from day 20 and gradually disappeared after 50 days, whereas the GFP–Gr-1+ cells that did not express BCR-ABL increased. Results represent the mean ± SD for each group (n ≥5). (F) Alox15 transgene rescues the defective CML phenotype. BCR-ABL and Alox15 were coexpressed in Alox15–/– BM cells by retroviral transduction, followed by transplantation of the transduced cells into recipient mice. Left: BCR-ABL and 15-LO were detected by Western blotting using antibodies against ABL and 15-LO in cells transfected with BCR-ABL-IRES-Alox15-pMSCV. Right: Kaplan-Meier survival curves for recipients of BCR-ABL-IRES-Alox15-pMSCV–transduced BM cells from Alox15–/– donor mice.