Área de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, IDISNA, Pamplona, Spain.
Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Pamplona, Spain.
Leukemia. 2021 May;35(5):1438-1450. doi: 10.1038/s41375-021-01147-y. Epub 2021 Feb 17.
Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.
多发性骨髓瘤（MM）是一种无法治愈的疾病，其临床异质性使其治疗具有挑战性，突出了需要生物学特征来指导改善的治疗方法。已经在 MM 中显示出特定长非编码 RNA（lncRNA）的失调，然而，完整的 lncRNA 转录组尚未阐明。在这项工作中，我们在 MM 样本中鉴定出了 40511 个新的 lncRNA。lncRNA 占 MM 转录组的 82%，其表达比编码基因更为异质。与正常骨髓浆细胞相比，MM 患者中共有 10351 个上调和 9535 个下调的 lncRNA。在正常 B 细胞成熟的背景下对 lncRNA 的转录动力学研究表明，在 MM 中有 989 个 lncRNA 具有独特的表达，其中 89 个表现出从头表观遗传激活。对这些 lncRNA 之一 SMILO（特异性骨髓瘤基因间长非编码 RNA）进行敲低研究，导致 MM 细胞增殖减少和凋亡诱导，并激活干扰素途径。我们还表明，lncRNA 的表达与临床和遗传风险改变一起，将 MM 患者分为几个无进展生存期和总生存期组。总之，我们对 lncRNA 转录组的全面分析揭示了存在与疾病的生物学和临床行为相关的特定 lncRNA。
