MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias
Abstract
Little is known about the expression levels or function of micro-RNAs (miRNAs) in normal and neoplastic cells, although it is becoming clear that miRNAs play important roles in the regulation of gene expression during development [Ambros, V. (2003) Cell 113, 673–676; McManus, M. T. (2003) Semin. Cancer Biol. 13, 253–258]. We now report the genomewide expression profiling of miRNAs in human B cell chronic lymphocytic leukemia (CLL) by using a microarray containing hundreds of human precursor and mature miRNA oligonucleotide probes. This approach allowed us to identify significant differences in miRNome expression between CLL samples and normal CD5+ B cells; data were confirmed by Northern blot analyses and real-time RT-PCR. At least two distinct clusters of CLL samples can be identified that were associated with the presence or absence of Zap-70 expression, a predictor of early disease progression. Two miRNA signatures were associated with the presence or absence of mutations in the expressed Ig variableregion genes or with deletions at 13q14, respectively. These data suggest that miRNA expression patterns have relevance to the biological and clinical behavior of this leukemia.
MicroRNAs (miRNAs) represent a class of small, functional, noncoding RNAs of 19–23 nt cleaved from ≈60- to 110-nt hairpin precursors (1, 2). Hundreds of miRNAs have been identified in plants and animals. The miRNAs are involved in various biological processes, including cell proliferation and cell death during development, stress resistance, and fat metabolism, through the regulation of gene expression (3). Some miRNAs, such as miR-15a or miR-16–1 (4, 5), are widely expressed, whereas others, such as miR-1 in mammalian heart (6, 7) or miR-223 in granulocytes and macrophages (5), are expressed in a tissue-specific manner. Little else is known about miRNA expression patterns or function in normal or neoplastic cells.
Understanding of the molecular pathogenesis of B cell chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is incomplete. We have shown previously that miR-15a and miR-16-1 are located at chromosome 13q14.3 within a 30-kb region of loss in CLL cells and that both genes are deleted and/or down-regulated in the majority of the analyzed CLL cell samples (4). These results provided the indication that deletion of miRNAs might be associated with a human malignancy. We also reported that 98 of the identified 186 miRNAs are located at fragile sites, minimal loss of heterozygosity regions, minimal regions of amplification, or common break-point regions in human cancers (8), suggesting that miRNAs might play a large and unanticipated role in the pathogenesis of human cancer.
For a complete list see Table 5. The name of each miRNA is as in the miRNA Registry, and the disregulation of either active molecule or precursor is specified in the name. The type of altered expression is presented in the last column.
For a complete list see Table 6. The name of each miRNA is as in the miRNA Registry, and the disregulation of either active molecule or precursor is specified in the name. The location in minimally deleted or minimally amplified or breakpoint regions or in fragile sites is presented. HCC, hepatocellular carcinoma; AML, acute myeloid leukemia; FRA, fragile site.
The name of each miRNA is as in the miRNA Registry, and the disregulation of either active molecule or precursor is specified in the name. IGVH, IgVH genes.
Acknowledgments
This work was supported by National Institutes of Health Grant P01-CA81534 (to the CLL Research Consortium), National Cancer Institute Grant CA076259, the Italian Ministero dell'Istruzione, dell'Universitae della Ricerca, and the Italian Ministero della Salute.
Notes
Abbreviations: miRNA, microRNA; CLL, chronic lymphocytic leukemia; MNC, mononuclear cells.
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