Characterization of the lncRNA Transcriptome in Multiple Myeloma

Abstract

Multiple myeloma (MM) is an hematological neoplasm characterized by uncontrolled clonal proliferation of plasma cells in the bone marrow. MM is an incurable and very heterogeneous disease, whose clinical variability makes its management challenging, highlighting the need for biological features to improve the therapy and survival of MM patients.

There are many studies about genetic and epigenetic alterations in MM; however, the magnitude of the heterogeneity of this neoplasm is still unknown. New approaches about the deregulation of specific long non-coding RNAs (lncRNAs) have been shown in MM; nevertheless, the complete lncRNA transcriptome has not yet been elucidated.

In this work, we have described the complete lncRNA transcriptome of MM patients in the context of B-cell differentiation. Thanks to our work, we identified 40,511 novel lncRNAs expressed in MM samples. We added to our group of novel lncRNAs all the coding genes and lncRNAs annotated before, detecting that 82% of the MM transcriptome corresponded to lncRNAs; and remarkably, 56% corresponded to the novel lncRNAs detected in MM patients. Furthermore, we identified that lncRNAs were more heterogeneously expressed than coding-genes.

After a comparison between MM samples and their healthy counterpart, bone marrow plasma cells (BMPCs) from healthy donors, we identified a group of 10,351 overexpressed and 9,535 downregulated lncRNAs in MM patients. Transcriptional dynamics study of those deregulated lncRNAs in the context of normal B-cell differentiation revealed a group of 989 lncRNAs with specific expression in MM samples, among which 89 showed de novo epigenomic activation.

From those 89 lncRNAs with specific expression and de novo gain active chromatin marks in MM, we selected SMILO for functional assays.

Knockdown studies on 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. These results showed the relevance of SMILO in the biology of MM cells, and that could be a potential therapeutic target.

We also analyzed the expression of lncRNAs in the context of the clinical of MM patients, looking for a better stratification and survival of patients. We studied the expression of the 89 lncRNAs with specific expression and de novo gain active chromatin marks in MM, together with high risk genetic and clinical alterations. Results revealed that lncRNAs together with different genetic and clinical factors could better stratify MM patients into different risk groups for progression-free survival and overall survival.

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.