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长链非编码 RNA 对小鼠急性髓系白血病和正常分化的需求。

lncRNA requirements for mouse acute myeloid leukemia and normal differentiation.

机构信息

Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.

Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, United States.

出版信息

Elife. 2017 Sep 6;6:e25607. doi: 10.7554/eLife.25607.

DOI:10.7554/eLife.25607
PMID:28875933
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5619947/
Abstract

A substantial fraction of the genome is transcribed in a cell-type-specific manner, producing long non-coding RNAs (lncRNAs), rather than protein-coding transcripts. Here, we systematically characterize transcriptional dynamics during hematopoiesis and in hematological malignancies. Our analysis of annotated and de novo assembled lncRNAs showed many are regulated during differentiation and mis-regulated in disease. We assessed lncRNA function via an in vivo RNAi screen in a model of acute myeloid leukemia. This identified several lncRNAs essential for leukemia maintenance, and found that a number act by promoting leukemia stem cell signatures. Leukemia blasts show a myeloid differentiation phenotype when these lncRNAs were depleted, and our data indicates that this effect is mediated via effects on the MYC oncogene. Bone marrow reconstitutions showed that a lncRNA expressed across all progenitors was required for the myeloid lineage, whereas the other leukemia-induced lncRNAs were dispensable in the normal setting.

摘要

大量基因组以细胞类型特异性的方式转录，产生长非编码 RNA（lncRNA），而不是蛋白质编码转录本。在这里，我们系统地描述了造血过程中和血液系统恶性肿瘤中的转录动力学。我们对注释和从头组装的 lncRNA 的分析表明，许多 lncRNA 在分化过程中受到调控，在疾病中失调。我们通过急性髓系白血病模型中的体内 RNAi 筛选评估了 lncRNA 的功能。这确定了几个对白血病维持至关重要的 lncRNA，并发现其中一些通过促进白血病干细胞特征来发挥作用。当这些 lncRNA 被耗尽时，白血病细胞会表现出髓样分化表型，我们的数据表明，这种效应是通过对 MYC 癌基因的影响来介导的。骨髓重建表明，一种在所有祖细胞中表达的 lncRNA 是髓系所必需的，而其他白血病诱导的 lncRNA 在正常情况下是可有可无的。

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