Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway.
Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway.
复制标题
Slug 的抑制通过 Slc13a3/ROS 信号通路有效靶向白血病干细胞。
DOI：
10.1038/s41375-019-0566-x
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发表时间：
2020
期刊：
影响因子：
11.4
通讯作者：
Wu,Wen-Shu
中科院分区：
文献类型：
--
作者：
Zhang,Zhonghui;Li,Lei;Wu,Chen;Yin,Guoshu;Zhu,Pei;Zhou,Yalu;Hong,Yuanfan;Ni,Hongyu;Qian,Zhijian;Wu,Wen-Shu
白血病干细胞 (LSC) 是罕见的急性髓系白血病 (AML) 细胞群，能够启动、维持和传播 AML。针对 LSC 是预防 AML 复发和改善长期结果的一种有前途的方法。虽然Slug是一种锌指转录抑制因子，可以负向调节正常造血干细胞的自我更新，但其在AML中的功能仍不清楚。我们在此报道，Slug 促进白血病发生，其缺失会损害 LSC 的自我更新并延缓白血病的进展。从机制上讲，Slc13a3是LSCs中Slug的直接靶标，限制LSCs的自我更新并显着延长受体的生存期。 SLUG 的遗传或药理学抑制或 Slc13a3 的强制表达可抑制人 AML 细胞的生长。总之，我们的研究表明，Slug 差异调节 LSC 和正常 HSC 的自我更新，Slug 和 Slc13a3 都是 LSC 的潜在治疗靶点。
Leukemia stem cells (LSCs) are the rare populations of acute myeloid leukemia (AML) cells that are able to initiate, maintain, and propagate AML. Targeting LSCs is a promising approach for preventing AML relapse and improving long-term outcomes. While Slug, a zinc-finger transcription repressor, negatively regulates the self-renewal of normal hematopoietic stem cells, its functions in AML are still unknown. We report here thatSlugpromotes leukemogenesis and its loss impairs LSC self-renewal and delays leukemia progression. Mechanistically,Slc13a3, a direct target of Slug in LSCs, restricts the self-renewal of LSCs and markedly prolongs recipient survival. Genetic or pharmacological inhibition of SLUG or forced expression of Slc13a3 suppresses the growth of human AML cells. In conclusion, our studies demonstrate that Slug differentially regulates self-renewal of LSCs and normal HSCs, and both Slug and Slc13a3 are potential therapeutic targets of LSCs.