Abstract
The PVT1 locus is identified as a cluster of T(2;8) and T(8;22) "variant" MYC-activating chromosomal translocation breakpoints extending 400 kb downstream of MYC in a subset (approximately 20%) of Burkitt's lymphoma (vBL). Recent reports that microRNAs (miRNA) may be associated with fragile sites and cancer-associated genomic regions prompted us to investigate whether the PVT1 region on chromosome 8q24 may contain miRNAs. Computational analysis of the genomic sequence covering the PVT1 locus and experimental verification identified seven miRNAs. One miRNA, hsa-miR-1204, resides within a previously described PVT1 exon (1b) that is often fused to the immunoglobulin light chain constant region in vBLs and is present in high copy number in MYC/PVT1-amplified tumors. Like its human counterpart, mouse mmu-miR-1204 represents the closest miRNA to Myc (~50 kb) and is found only 1 to 2 kb downstream of a cluster of retroviral integration sites. Another miRNA, mmu-miR-1206, is close to a cluster of variant translocation breakpoints associated with mouse plasmacytoma and exon 1 of mouse Pvt1. Virtually all the miRNA precursor transcripts are expressed at higher levels in late-stage B cells (including plasmacytoma and vBL cell lines) compared with immature B cells, suggesting possible roles in lymphoid development and/or lymphoma. In addition, lentiviral vector-mediated overexpression of the miR-1204 precursor (human and mouse) in a mouse pre-B-cell line increased expression of Myc. High levels of expression of the hsa-miR-1204 precursor is also seen in several epithelial cancer cell lines with MYC/PVT1 coamplification, suggesting a potentially broad role for these miRNAs in tumorigenesis.
Highlights
Noncoding RNAs have represented an exception to the ‘‘Central Dogma’’ theory that RNA predominately encodes protein
The absence of involvement of any protein-encoding gene in this region coupled with the location of hsa-miR-15 and hsa-miR-16 within a 30-kb – deleted segment in chronic lymphocytic leukemia has suggested that, at least in this context, these miRNAs can function as tumor suppressors [4]
The study of unstable genomic regions has been widely used to identify loci contributing to disease processes, cancer
Summary
Noncoding RNAs have represented an exception to the ‘‘Central Dogma’’ theory that RNA predominately encodes protein. Analysis of the distribution of miRNA genes in the human genome has suggested that many are found within genomically unstable regions. This finding has strengthened the argument that deregulated expression of miRNAs and/or their targets could be critical components in many disease processes, including cancer [2]. A cluster of miRNAs resides on human chromosome 13q14, a frequently deleted chromosomal region in cancer [3]. The absence of involvement of any protein-encoding gene in this region coupled with the location of hsa-miR-15 and hsa-miR-16 within a 30-kb – deleted segment in chronic lymphocytic leukemia has suggested that, at least in this context, these miRNAs can function as tumor suppressors [4]. Other miRNAs that have been implicated in cancer include hsa-let-7, hsamir-155, and a cluster of miRNAs found within chromosome 13q31 that are frequently amplified in tumors from patients with various forms of lymphoma [5,6,7,8,9]
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