Abstract
Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs (scaRNAs) are non-coding RNAs involved in the maturation of other RNA molecules and generally located in the introns of host genes. It is now emerging that altered sno/scaRNAs expression may have a pathological role in cancer. This study elucidates the patterns of sno/scaRNAs expression in multiple myeloma (MM) by profiling purified malignant plasma cells from 55 MMs, 8 secondary plasma cell leukemias (sPCLs) and 4 normal controls. Overall, a global sno/scaRNAs downregulation was found in MMs and, even more, in sPCLs compared with normal plasma cells. Whereas SCARNA22 resulted the only sno/scaRNA characterizing the translocation/cyclin D4 (TC4) MM, TC2 group displayed a distinct sno/scaRNA signature overexpressing members of SNORD115 and SNORD116 families located in a region finely regulated by an imprinting center at 15q11, which, however, resulted overall hypomethylated in MMs independently of the SNORD115 and SNORD116 expression levels. Finally, integrative analyses with available gene expression and genome-wide data revealed the occurrence of significant sno/scaRNAs/host genes co-expression and the putative influence of allelic imbalances on specific snoRNAs expression. Our data extend the current view of sno/scaRNAs deregulation in cancer and add novel information to the bio-molecular complexity of plasma cell dyscrasias.
Highlights
Multiple myeloma (MM) is a fatal B-cell malignancy characterized by a heterogeneous clinical course and a remarkable genomic instability that encompasses a large array of structural and numerical chromosomal aberrations.[1]
Global sno/small Cajal body-specific RNA (scaRNA) expression profiling in MM patients The expression profiles of sno/scaRNA genes have been investigated in a panel of 55 MMs, 8 secondary plasma cell leukemias (sPCLs) and 4 normal tonsil Plasma cells (PCs)
To determine whether the natural grouping of global sno/scaRNA expression profiling could be associated with specific molecular groups, we performed an unsupervised analysis using conventional hierarchical agglomerative clustering of the 115 small nucleolar RNAs (snoRNAs) and 13 scaRNAs whose average change in expression levels varied at least 1.5-fold from the mean across the data set (Figure 1)
Summary
Multiple myeloma (MM) is a fatal B-cell malignancy characterized by a heterogeneous clinical course and a remarkable genomic instability that encompasses a large array of structural and numerical chromosomal aberrations.[1]. In addition to highly abundant and functionally important transfer and ribosomal RNAs (tRNA and rRNA), ncRNAs include a large variety of molecules such as microRNAs (miRNAs), short interfering RNAs, piwi-associated RNAs, small nucleolar RNAs (snoRNAs), small Cajal body-specific RNAs (scaRNAs), small nuclear RNAs (snRNAs) and long ncRNAs that are still only partially understood.[4] Among these, miRNAs have been extensively studied in carcinogenesis.[4] In the context of MM, we and other authors have recently shown that deregulated patterns of miRNA’s expression are associated with distinct clinical and molecular entities of disease, giving evidence of their pathogenetic role.[5,6]. Chu et al.[12] reported the upregulation of SCARNA22 in MMs harboring the t(4;14); notably, this scaRNA is localized within intron 18 of the WHSC1/MMSET gene involved in the translocation and constitutively expressed in these patients These authors provided experimental evidence that SCARNA22 can suppress oxidative stress both in vitro and in vivo, facilitate cell. Twenty-five of the 63 MM/sPCL samples profiled for sno/scaRNA expression were used for genome-wide DNA analysis using Affymetrix GeneChip Human Mapping 50K XbaI microarrays as previously reported by us.[13]
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