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 3

Inhibition of Alox15 impairs LSCs and prolongs survival of CML mice.

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Inhibition of Alox15 impairs LSCs and prolongs survival of CML mice. (A)...
(A) PD146176 inhibited LSCs in vitro. BM cells from CML mice were cultured (2 × 106 cells per well in a 6-well plate) under stem cell conditions in the presence of DMSO or PD146176 for 3 days, followed by FACS analysis of LSCs and CMPs (GFP+Lin–Sca-1–c-Kit+). Results represent the mean ± SD. (B) PD146176 inhibited LSC survival in CML mice. CML mice were treated with placebo or PD146176, and at day 14 after CML induction, the percentages of BM LSCs in the treated CML mice were compared. A no-treatment control was used for FACS analysis. (C) PD146176 induced apoptosis of LSCs in CML mice. On day 14 after CML induction, BM cells from placebo- or PD146176-treated CML mice were stained with 7AAD and annexin V, and the percentage of double-positve LSCs was determined by FACS. Results represent the mean ± SD. (D) Kaplan-Meier survival curves for CML mice treated with placebo or with PD146176 alone. Inhibition of Alox15 by PD146176 significantly prolonged survival of the CML mice (n = 4 for each group). (E) In PD146176-treated CML mice, the effectiveness of PD146176 in treating CML mice correlated with a decreased percentage of GFP+Gr-1+ leukemia cells in PB. FACS analysis showed the disappearance of GFP+Gr-1+ cells in the PB of CML mice treated with PD146176. Results represent the mean ± SD. (F) Photomicrographs of H&E-stained lung and spleen sections from CML mice treated with placebo or PD146176. Scale bars: 100 μM (top); 50 μM (bottom). *P < 0.05; **P < 0.01.