miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.
miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.
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DOI：
10.1016/j.ccell.2015.12.011
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发表时间：
2016-02-08
期刊：
影响因子：
50.3
通讯作者：
Dick JE
中科院分区：
文献类型：
--
作者：
Lechman ER;Gentner B;Ng SW;Schoof EM;van Galen P;Kennedy JA;Nucera S;Ciceri F;Kaufmann KB;Takayama N;Dobson SM;Trotman-Grant A;Krivdova G;Elzinga J;Mitchell A;Nilsson B;Hermans KG;Eppert K;Marke R;Isserlin R;Voisin V;Bader GD;Zandstra PW;Golub TR;Ebert BL;Lu J;Minden M;Wang JC;Naldini L;Dick JE
为了研究人类急性髓系白血病 (AML) 干细胞 (LSC) 中的 miRNA 功能，我们从经过功能验证的 AML 样本亚群中生成了与预后 LSC 相关的 miRNA 特征。对于一种标志性 miRNA，即 miR-126，其高生物活性将所有体内患者样本 LSC 活性聚集到单个分类群体中，将 miR-126 表达与 LSC 功能紧密耦合。通过功能研究，发现 miR-126 可以抑制细胞周期进程、阻止分化并增加体内原代 LSC 的自我更新。与先前显示 miR-126 调节正常造血干细胞 (HSC) 循环的结果相比，LSC 和 HSC 之间的这些功能性干细胞效应相反。转录组和蛋白质组组合分析表明，miR-126 靶向 PI3K/AKT/MTOR 信号通路，保持 LSC 静止并促进化疗耐药。 AML 的临床结果与 LSC 相关 miRNA 表达相关 miR-126 靶向 PI3K/AKT/MTOR 信号通路的多个组成部分 miR-126 通过将 LSC 保持在静止状态来促进化疗耐药性 miR-126 控制正常和恶性干细胞中相反的自我更新结果 Lechman 等人。研究表明，miR-126 靶向 PI3K/AKT/MTOR 信号通路，以保持急性髓系白血病干细胞 (LSC) 的静止状态、增强自我更新并促进化疗耐药。与扩增正常造血干细胞相比，降低 miR-126 水平会损害 LSC 的维持。
To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance. Clinical outcome in AML correlates with LSC-associated miRNA expression miR-126 targets multiple components of the PI3K/AKT/MTOR signaling pathway miR-126 promotes chemotherapy resistance by preserving LSC in a quiescent state miR-126 governs opposing self-renewal outcomes in normal and malignant stem cells Lechman et al. show that miR-126 targets the PI3K/AKT/MTOR signaling pathway to preserve quiescence, increase self-renewal, and promote chemotherapy resistance of acute myeloid leukemia stem cells (LSC). Reducing the miR-126 level impairs LSC maintenance in contrast to expanding normal hematopoietic stem cells.