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

• Published in: Nature genetics Vol. 41; no. 7; pp. 783 - 792
• Main Authors: Zhang, Haojian, Peng, Cong, Chen, Yaoyu, Li, Shaoguang, Hu, Yiguo
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2009; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cancer; Cancer Research; Chronic myeloid leukemia; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genes; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - metabolism; Human Genetics; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplastic Stem Cells - enzymology; Neoplastic Stem Cells - metabolism; Physiological aspects; Prevention; Stem cells; Studies; United States; Chronic myelogenous leukemia; Myeloproliferative syndrome; Malignant hemopathy; Gene; Stem cell; Cancer
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.389

Shaoguang Li and colleagues identify Alox5 as a key gene that regulates the function of leukemia stem cells but not normal hematopoietic stem cells in mice, highlighting how cancer and normal stem cells distinctly self-renew and differentiate. 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.