Ronchetti Domenica, Agnelli Luca, Taiana Elisa, Galletti Serena, Manzoni Martina, Todoerti Katia, Musto Pellegrino, Strozzi Francesco, Neri Antonino
Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy.
Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
Oncotarget. 2016 Mar 22;7(12):14814-30. doi: 10.18632/oncotarget.7442.
Although many efforts have recently contributed to improve our knowledge of molecular pathogenesis of multiple myeloma (MM), the role and significance of long non-coding RNAs (lncRNAs) in plasma cells (PC) malignancies remains virtually absent. To this aim, we developed a custom annotation pipeline of microarray data investigating lncRNA expression in PCs from 20 monoclonal gammopathies of undetermined significance, 33 smoldering MM, 170 MM, and 36 extra-medullary MMs/plasma cell leukemia patients, and 9 healthy donors. Our study identified 31 lncRNAs deregulated in tumor samples compared to normal controls; among these, the upregulation of MALAT1 appeared associated in MM patients with molecular pathways involving cell cycle regulation, p53-mediated DNA damage response, and mRNA maturation processes. Furthermore, we found 21 lncRNAs whose expression were progressively deregulated trough the more aggressive stages of PC dyscrasia, suggesting a possible role in the progression of the disease. Finally, in the context of molecular heterogeneity of MM, we identified a transcriptional fingerprint in hyperdiploid patients, characterized by the upregulation of lncRNAs/pseudogenes related to ribosomal protein genes, known to be upregulated in this molecular group. Overall, the data provides an important resource for future studies on the functions of lncRNAs in the pathology.
尽管最近有许多研究致力于增进我们对多发性骨髓瘤(MM)分子发病机制的了解,但长链非编码RNA(lncRNA)在浆细胞(PC)恶性肿瘤中的作用和意义仍几乎未被涉及。为此,我们开发了一种定制的微阵列数据注释流程,以研究20例意义未明的单克隆丙种球蛋白病、33例冒烟型MM、170例MM以及36例髓外MM/浆细胞白血病患者和9名健康供体的PC中lncRNA的表达情况。我们的研究发现,与正常对照相比,肿瘤样本中有31种lncRNA表达失调;其中,MALAT1的上调在MM患者中似乎与涉及细胞周期调控、p53介导的DNA损伤反应和mRNA成熟过程的分子途径相关。此外,我们发现21种lncRNA的表达在PC发育异常的更侵袭性阶段逐渐失调,提示其在疾病进展中可能发挥作用。最后,在MM分子异质性的背景下,我们在超二倍体患者中鉴定出一种转录指纹,其特征是与核糖体蛋白基因相关的lncRNA/假基因上调,已知该分子组中这些基因会上调。总体而言,这些数据为未来lncRNA在病理学中功能的研究提供了重要资源。