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Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia

Nature Genetics volume 41, pages 783–792 (2009)Cite this article

Abstract

Targeting of cancer stem cells is believed to be essential for curative therapy of cancers, but supporting evidence is limited. Few selective target genes in cancer stem cells have been identified. Here we identify the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) as a critical regulator for leukemia stem cells (LSCs) in BCR-ABL–induced chronic myeloid leukemia (CML). In the absence of Alox5, BCR-ABL failed to induce CML in mice. This Alox5 deficiency caused impairment of the function of LSCs but not normal hematopoietic stem cells (HSCs) through affecting differentiation, cell division and survival of long-term LSCs (LT-LSCs), consequently causing a depletion of LSCs and a failure of CML development. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs similarly by affecting LT-LSCs, and prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells and its inhibition can completely inhibit the function of these stem cells.

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Figure 1: Alox5 is essential for the induction of CML by BCR-ABL.
Figure 2: Alox5 transgene rescues defective CML phenotype.
Figure 3: Loss of Alox5 impairs the function of CML stem cell.
Figure 4: Loss of Alox5 function blocks differentiation of LT-LSCs.
Figure 5: Inhibition of Alox5 prolongs survival of CML mice.
Figure 6: Alox5 deficiency does not significantly affect normal HSCs.
Figure 7: Alox5 is not required for the induction of lymphoid leukemia by BCR-ABL.

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Acknowledgements

This work was supported by the grants from the Leukemia & Lymphoma Society and the National Institutes of Health (R01-CA122142, R01-CA114199) to S.L. S.L. is a Scholar of the Leukemia & Lymphoma Society.

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  1. Yiguo Hu

    Present address: Present address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Yaoyu Chen, Haojian Zhang, Cong Peng & Shaoguang Li

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Contributions

Y.C. designed and performed experiments, and analyzed the data; Y.H. performed experiments and analyzed the data; H.Z. performed experiments; C.P. helped with the experiments; S.L. designed and performed experiments, analyzed the data and wrote the paper.

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Correspondence to Shaoguang Li.

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Chen, Y., Hu, Y., Zhang, H. et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet 41, 783–792 (2009). https://doi.org/10.1038/ng.389

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