Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma

Abstract

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.

Transcriptome analysis of the lncRNAs and their mRNA networks associated with multiple myeloma

“…The signi cance of the characteristics of complete lncRNAs transcriptome in MM was also analyzed by Carrasco-Leon et al, 40511 novel lncRNAs have been identi ed in MM samples, accounts for 82% of the MM transcriptional group, which is more heterogeneously expressed than the coding gene. Compared with normal bone marrow plasma cells, a total of 10351 overexpressed and 9535 down-regulated lncRNAs were identi ed in MM patients [33] . However, there were no reports on the differentially expressed lncRNAs and their cis-regulated target mRNAs in healthy adults, newly diagnosed MM, and relapsed MM.…”

Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications

“…One example of the latter is SMILO (specific myeloma intergenic long noncoding RNA), which, due to loss of DNA methylation, becomes epigenetically activated. The activation of SMILO results in its overexpression and promotes MM cell survival via the changing expression of the genes involved in nucleosome assembly, nonsense-mediated decay, chromatin silencing and cell adhesion [62]. Overall, SMILO overexpression in MM has antiapoptotic and pro-proliferative effects due to the suppression of several interferonstimulated genes (ISGs-ISG15, IFI27 and MX1).…”

Identification of novel long noncoding RNA with distinct expression patterns in different subtypes of multiple myeloma

“…[25] Additionally, studies have revealed how the knockdown or upregulation of certain lncRNAs is also associated with different biological and phenotypic effects in MM cells, such as decrease in cell proliferation or viability, decrease in cellular migration, increase in cellular apoptosis and cell cycle arrest indicating possible roles for lncRNAs in the pathobiology of MM. [26] Further, an increasing number of studies have indicated that the abnormal expression of certain lncRNAs is linked to the overall survival (OS), and the progression free survival (PFS) of patients with myeloma [27] leading to identi cation of long noncoding RNAs as potential novel biomarkers for predicting patient's outcome [28,29] and potential drug targets.…”