Gene expression profiling in WT and Alox15-/- HSCs. Mus musculus

To understand the underlying mechanism by which Alox15 gene is required by HSCs, we performed a comparative DNA microarray analysis using total RNA isolated from wild type Lin-Sca-1+c-Kit+, Alox5-/- Lin-Sca-1+c-Kit+. The result was validated by quantitative real-time PCR analysis of wild type Lin-Sca-1+c-Kit+ and Alox15-/- Lin-Sca-1+c-Kit+. Cancer stem cells are responsible for the initiation and maintenance of some types of cancer, and few effective target genes in these stem cells have been identified. Here we show that the arachidonate 15-lipoxygenase gene (Alox15) is essential for the survival of leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL failed to induce CML in mice. This Alox15 deficiency caused the impairment of LSC function through affecting cell division and apoptosis, leading to eventual deletion of LSCs. Inhibition of Alox15 function by a chemical compound also impaired the function of LSCs, and cured CML mice. In addition, we show that Alox15 is required for the survival of human CD34+ CML stem cells. The defective CML phenotype in the absence of Alox15 is rescued by depleting P-selectin. The underlying mechanisms are also related to pathways involving PTEN, PI3K/AKT, and ICSBP. These results identify Alox15 as a potential target gene for eradicating LSCs in CML, providing a novel strategy for treating CML patients for cure. Overall design: we compared the gene profile of HSCs between WT mice and Alox15-/- mice.