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 2

Loss of Alox15 impairs LSC function.

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Loss of Alox15 impairs LSC function. (A) FACS analysis showed that loss ...
(A) FACS analysis showed that loss of Alox15 caused a significant reduction of LSCs in the BM of CML mice (P < 0.05) and a smaller reduction of normal HSCs (GFP–Lin–c-Kit+Sca-1+) at days 14 and 20 after CML induction. Results represent the mean ± SD. (B) Loss of Alox15 caused a more significant reduction of BCR-ABL–expressing (GFP+) (left panel) than of non-BCR-ABL–expressing (GFP–) (right panel) CMP, GMP, and MEP cells in the BM of CML mice (n = 4). Results represent the mean ± SD. (C) WT (CD45.1) and Alox15–/– (CD45.2) BM cells from CML mice were 1:1 mixed and transplanted into lethally irradiated secondary recipient mice. At days 14 and 20, the percentage of CD45.1+ cells was much higher than that of CD45.2+ cells. Results represent the mean ± SD. (D) Cell cycle analysis showed a higher percentage of LSCs in the S + G2/M phase in BM cells of Alox15–/– versus WT CML mice. BM cells were stained with Hoechst blue for FACS analysis. The mean percentage for each cell population (n = 5) is shown. (E) Alox15 deficiency caused increased apoptosis of LSCs over normal HSCs by staining the cells with 7AAD and annexin V. Results represent the mean ± SD. (F and G) Alox15 deficiency impaired the function of BCR-ABL–expressing BM cells in secondary recipient mice receiving 2 × 106 BCR-ABL–transduced WT (n = 3) or Alox15–/– (n = 4) BM cells per mouse. Alox15 deficiency significantly inhibited BCR-ABL–expressing blood cells (GFP+) (F) and prevented CML development (G). Results represent the mean ± SD (**P < 0.01).