Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival
Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival
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DOI：
10.1172/jci66129
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发表时间：
2014-09-01
影响因子：
15.9
通讯作者：
Li, Shaoguang
中科院分区：
文献类型：
--
作者：
Chen, Yaoyu;Peng, Cong;Li, Shaoguang
癌症干细胞（CSC）负责某些类型癌症的发生和维持，这表明抑制这些细胞可能会限制疾病的进展和复发。不幸的是，目前已鉴定出很少的 CSC 特异性基因。在这里，我们确定编码花生四烯酸 15-脂氧合酶 (Alox15/15-LO) 的基因对于 BCR-ABL 诱导的慢性粒细胞白血病 (CML) 小鼠模型中白血病干细胞 (LSC) 的存活至关重要。在缺乏 Alox15 的情况下，BCR-ABL 无法诱导小鼠 CML。此外，Alox15 缺失通过影响细胞分裂和凋亡来损害 LSC 功能，最终导致 LSC 耗尽。此外，对 15-LO 功能的化学抑制会损害小鼠的 LSC 功能并减弱 CML。 Alox15 缺陷动物中的 CIVIL 表型缺陷可以通过消除编码 P-选择素的基因来挽救，该基因在 Alox15 缺陷动物中表达上调。 P-选择素的缺失和过度表达都会影响LSC的存活。在人类 CML 细胞系和 CD34(+) 细胞中，敲除 Alox15 或抑制 15-LO 会显着降低存活率。 Alox15 的缺失会改变 PTEN、PI3K/AKT 和转录因子 ICSBP 的表达，这些都是已知的癌症发病机制介质。这些结果表明 ALOX15 有潜力作为根除 CML 中 LSC 的治疗靶点。
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.