Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides. Due to modern genomic techniques, the involvement of lncRNAs in tumorigenesis has been revealed; however, information concerning lncRNA interplay in multiple myeloma (MM) and plasma cell leukemia (PCL) is virtually absent. Herein, we aimed to identify the lncRNAs involved in MM to PCL progression. We investigated representative datasets of MM and PCL patients using next-generation sequencing. In total, 13 deregulated lncRNAs (p < 0.00025) were identified; four of them were chosen for further validation in an independent set of MM and PCL patients by RT-qPCR. The obtained results proved the significant downregulation of lymphocyte antigen antisense RNA 1 (LY86-AS1) and VIM antisense RNA 1 (VIM-AS1) in PCL compared to MM. Importantly, these two lncRNAs could be involved in the progression of MM into PCL; thus, they could serve as promising novel biomarkers of MM progression.

• Keywords
• biomarkers, disease progression, long non-coding RNA, multiple myeloma, next-generation sequencing, plasma cell leukemia,
• Publication type
• Journal Article MeSH

B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.

• MeSH
• Adenine analogs & derivatives   pharmacology   MeSH
• CD40 Antigens genetics   metabolism   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell drug therapy   genetics   metabolism   pathology   MeSH
• Adult MeSH
• TNF Receptor-Associated Factor 4 genetics   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• MicroRNAs genetics   MeSH
• Survival Rate MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Tumor Cells, Cultured MeSH
• Follow-Up Studies MeSH
• Piperidines pharmacology   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins c-bcr antagonists & inhibitors   MeSH
• Proto-Oncogene Proteins c-myc genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenine MeSH
• CD40 Antigens MeSH
• BCR protein, human MeSH Browser
• TNF Receptor-Associated Factor 4 MeSH
• ibrutinib MeSH Browser
• MicroRNAs MeSH
• MIRN29a microRNA, human MeSH Browser
• MYC protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Piperidines MeSH
• Proto-Oncogene Proteins c-bcr MeSH
• Proto-Oncogene Proteins c-myc MeSH
• TRAF4 protein, human MeSH Browser