4.8 Article

Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 9, 页码 3847-3862

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI66129

关键词

-

资金

  1. Leukemia & Lymphoma Society
  2. NIH [R01-CA122142, R01-CA114199]
  3. Leukaemia & Lymphoma Research UK [LLR 08071, 13035]
  4. Kay Kendall Leukaemia Fund grant [KKL501]
  5. Glasgow Experimental Cancer Medicine Centre (ECMC)
  6. Cancer Research UK
  7. Chief Scientist's Office (Edinburgh, United Kingdom)
  8. Cancer Research UK [11008] Funding Source: researchfish

向作者/读者索取更多资源

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 CIVIL 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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据