A distinct set of long non-coding RNAs in childhood MLL-rearranged acute lymphoblastic leukemia: biology and epigenetic target
A distinct set of long non-coding RNAs in childhood MLL-rearranged acute lymphoblastic leukemia: biology and epigenetic target
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DOI：
10.1093/hmg/ddu040
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发表时间：
2014-06-15
影响因子：
3.5
通讯作者：
Chen, Yue-Qin
中科院分区：
文献类型：
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作者：
Fang, Ke;Han, Bo-Wei;Chen, Yue-Qin
最近发现，长非编码RNA(LncRNAs)在人类基因组中广泛转录，并与多种人类疾病有关。然而，有关lncRNAs在血液系统恶性肿瘤中的表达模式和调控作用的研究尚未见报道。在这里，我们开展了MLL重排急性淋巴细胞白血病(MLL-r ALL)的全基因组lncRNA表达研究，并建立了lncRNA/信使RNA共表达网络，以深入了解这些调控异常的lncRNA的生物学作用。我们检测了一些在MLL-r ALL样本中与MLL-r野生型相比差异表达的lncRNA，并鉴定了不同易位的MLL-r亚型之间以及婴儿MLL-r ALL与其他MLL-r ALL患者之间独特的lncRNA表达模式，提示它们可能成为该病的新的生物标志物。重要的是，鉴定了几个与膜蛋白基因相对应的lncRNAs，包括一个溶酶体相关的膜蛋白。膜蛋白与MLL-r白血病之间的这种联系以前还没有报道过。令人印象深刻的是，功能分析表明，有几个lncRNAs对应于MLL融合蛋白靶基因的表达，包括HOXA9、Meis1等，还有一些与组蛋白相关功能或膜蛋白相关。进一步的实验表明，一些LncRNAs对MLL-r白血病细胞的凋亡和增殖的影响与共表达的HOXA基因簇有关。最后，还发现了一组受H3K79甲基化表观遗传调控的lncRNAs。这些发现可能对参与MLL-r白血病启动的lncRNAs的机制提供新的见解。这是第一个将lncRNAs与白血病发生联系起来的研究。
Long non-coding RNAs (lncRNAs) have been recently found to be pervasively transcribed in human genome and link to diverse human diseases. However, the expression patterns and regulatory roles of lncRNAs in hematopoietic malignancies have not been reported. Here, we carried out a genome-wide lncRNA expression study in MLL-rearranged acute lymphoblastic leukemia (MLL-r ALL) and established lncRNA/messenger RNA coexpression networks to gain insight into the biological roles of these dysregulated lncRNAs. We detected a number of lncRNAs that were differentially expressed in MLL-r ALL samples compared with MLL-r wild-type and identified unique lncRNA expression patterns between MLL-r subtypes with different translocations as well as between infant MLL-r ALL with other MLL-r ALL patients, suggesting that they might be served as novel biomarkers for the disease. Importantly, several lncRNAs that correspond with membrane protein genes, including a lysosome-associated membrane protein, were identified. No such link between the membrane proteins and MLL-r leukemia has been reported previously. Impressively, the functional analysis showed that several lncRNAs corresponded to the expression of MLL-fusion protein target genes, including HOXA9, MEIS1, etc., while some other associated with histone-related functions or membrane proteins. Further experiments characterize the effect of some lncRNAs on MLL-r leukemia apoptosis and proliferation as the function of the coexpressed HOXA gene cluster. Finally, a set of lncRNAs epigenetically regulated by H3K79 methylation were also discovered. These findings may provide novel insights into the mechanisms of lncRNAs involved in the initiation of MLL-r leukemia. This is the first study linking lncRNAs to leukemogenesis.