Karyotype-specific microRNA signature in chronic lymphocytic leukemia

Abstract

Chromosomal abnormalities, immunoglobulin heavy chain variable-region (IGHV) gene mutation status, and zeta-associated protein 70 (ZAP-70) expression levels have independent prognostic relevance in chronic lymphocytic leukemia (CLL); however, their concordance is variable. Because deregulation of microRNAs has been linked to disease initiation and progression in CLL, we studied the value of the microRNAs as a signature for CLL patients with specific chromosomal abnormalities. We identified 32 microRNAs able to discriminate the 11q deletion, 17p deletion, trisomy 12, 13q deletion, and normal karyotype cytogenetic subgroups. The expression values of 9 among the 32 microRNAs (miR-151-3p, miR-34a, miR-29c, miR-29b, miR-155, miR-148a, miR-146a, miR-146b5p, and miR-640) were correlated with gene expression data from the same samples to assess their biologic impact on CLL. In this study we also found that IGHV unmutated, high expression of ZAP-70 protein, and low expression of the miR-223, miR-29c, miR-29b, and miR-181 family were strongly associated with disease progression in CLL cases harboring 17p deletion, whereas in those harboring trisomy 12 only high expression of the miR-181a, among the analyzed parameters, suggested more aggressive disease. Thus, the use of the microRNA-based classifications may yield clinically useful biomarkers of tumor behavior in CLL.

Figure 1

miRNAs differentially expressed among cytogenetic groups of CLL. MiRNAs' relative expression in CLL samples with different karyotypes was determined by Taqman qRT PCR assay. Each data sample was normalized to the endogenous reference RNU6B by use of the 2^−Δct method. The relative expression values were used to design box and whisker plots. Crosses in the boxes indicate outlier points. ⁺P value is the result of either Kruskal-Wallis or ANOVA. The ANOVA test was used only for miR-29b. The homogeneity of the samples variance was defined by use of the Bartlett test.