Small nucleolar RNAs as new biomarkers in chronic lymphocytic leukemia

Abstract

Background: Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs are non-coding RNAs involved in the maturation of other RNA molecules. Alterations of sno/scaRNA expression may play a role in cancerogenesis. This study elucidates the patterns of sno/scaRNA expression in 211 chronic lymphocytic leukemia (CLL) patients (Binet stage A) also in comparison with those of different normal B-cell subsets.

Methods: The patterns of sno/scaRNA expression in highly purified CD19+ B-cells of 211 CLL patients and in 18 normal B-cell samples--6 from peripheral blood, and 12 from tonsils (4 germinal center, 2 marginal zone, 3 switched memory and 3 naïve B-cells)--were analyzed on the Affymetrix GeneChip® Human Gene 1.0 ST array.

Results: CLLs display a sno/scaRNAs expression profile similar to normal memory, naïve and marginal-zone B-cells, with the exception of a few down-regulated transcripts (SNORA31, -6, -62, and -71C). Our analyses also suggest some heterogeneity in the pattern of sno/scaRNAs expression which is apparently unrelated to the major biological (ZAP-70 and CD38), molecular (IGHV mutation) and cytogenetic markers. Moreover, we found that SNORA70F was significantly down-regulated in poor prognostic subgroups and this phenomenon was associated with the down-regulation of its host gene COBLL1. Finally, we generated an independent model based on SNORA74A and SNORD116-18 expression, which appears to distinguish two different prognostic CLL groups.

Conclusions: These data extend the view of sno/scaRNAs deregulation in cancer and may contribute to discover novel biomarkers associated with the disease and potentially useful to predict the clinical outcome of early stage CLL patients.

Figure 1

sno/scaRNA expression profile of CLL and normal B-cells. A PCA analysis that includes CLL samples shows that CLLs are closer in a three-dimensional space of similarity to SM, N and MZ tonsillar B-lymphocytes than to other B-cell types, based on the expression of 215 snoRNA and 17 scaRNA genes (A). Heatmap of the differentially expressed sno/scaRNAs in CLL patients, N-SM-MZ B-cells, and GC B-cells. snoRNAs also resulting from two-class supervised analysis comparing CLL and N-SM-MZ B-cells group, are marked with an asterisk (B).

Figure 2

PFS of patients grouped according to the snoRNAs-based model. Kaplan-Meier curves of the 2 groups defined by the 2-snoRNAs model identifying a low-risk group characterized by the low expression of both snoRNAs and a high risk group characterized by the high expression of at least one of the two snoRNAs. The high risk group has a median PFS of 39 months.