Abstract：
Genetic and/or epigenetic alterations in hematopoietic stem cells (HSCs) contribute to leukemia stem cell (LSC) formation. We aimed to identify alterations in the lncRNA expression profile signature of LSCs upon inhibition of PI3K/Akt/mTOR signaling, which provides selective advantages to LSCs. We also aimed to elucidate the potential interaction networks and functions of differentially expressed lncRNAs (DELs). We suppressed PI3K/Akt/mTOR signaling in LSC and HSC cell-lines by specific PI3K/mTOR dual-inhibitor (VS-5584) and confirmed the inhibition by antibody-array. We defined DELs by qRT-PCR. Increased SRA, ZEB2-AS1, antiPeg11, DLX6-AS, SNHG4, and decreased H19, PCGEM1, CAR-Intergenic-10, L1PA16, IGF2AS, and SNHG5 levels (|log2fold-change|>5) were strictly associated with PI3K/Akt/mTOR pathway inhibition in LSC. We performed in silico analyses for DELs. ZEB2-AS1 was found to be specifically expressed in normal bone marrow and predominantly lower in leukemic cell-lines. Three sub-clusters were identified for DELs and they were associated with \"abnormality of multiple cell lineages in the bone marrow.\" DELs were most highly enriched for \"glucuronidation\" Reactome pathway and \"ascorbate and aldarate metabolism\" and \"inositol phosphate metabolism\" KEGG pathways. Transcription factors, MBD4, NANOG, PAX6, RELA, CEBPB, and CEBPA were predicted to be associated with the DEL profile. SRA was predicted to interact with CREB1, RARA, and PPARA. The possible DELs\' targets were predicted to form six ontological groups, be highly enriched for phosphoprotein, and be involved in \"PPAR signaling pathway\" and \"ChREBP regulation by carbohydrates and cAMP.\" These results will help to elucidate the roles of lncRNAs in the mechanisms that provide selective advantages to leukemia stem cells.
摘要：
造血干细胞(HSC)中的遗传和/或表观遗传改变有助于白血病干细胞(LSC)形成。我们旨在鉴定LSCs在抑制PI3K/Akt/mTOR信号后的lncRNA表达谱特征的改变，这为LSCs提供了选择性优势。我们还旨在阐明差异表达的lncRNAs（DELs）的潜在相互作用网络和功能。我们通过特异性PI3K/mTOR双重抑制剂（VS-5584）抑制了LSC和HSC细胞系中的PI3K/Akt/mTOR信号传导，并通过抗体阵列证实了这种抑制作用。我们通过qRT-PCR定义DEL。增加SRA,ZEB2-AS1,antiPeg11,DLX6-AS,SNHG4，并降低H19，PCGEM1，CAR-Intergenic-10，L1PA16，IGF2AS，SNHG5水平(|log2倍变化|>5)与LSC中PI3K/Akt/mTOR通路抑制严格相关。我们对DEL进行了计算机模拟分析。发现ZEB2-AS1在正常骨髓中特异性表达，在白血病细胞系中主要较低。为DEL确定了三个亚簇，它们与骨髓中多个细胞谱系的异常有关。“DEL在“葡糖醛酸化”Reactome途径和“抗坏血酸和醛酸代谢”和“肌醇磷酸代谢”KEGG途径中的富集程度最高。转录因子,MBD4,NANOG,PAX6,RELA,CEBPB,和CEBPA预测与DEL概况相关。预测SRA与CREB1、RARA、和PPARA。预计可能的DEL目标将形成六个本体论组，高度富集磷蛋白，并参与碳水化合物和cAMP对“PPAR信号通路”和“ChREBP的调节。“这些结果将有助于阐明lncRNAs在为白血病干细胞提供选择性优势的机制中的作用。
