Huppi Konrad, Volfovsky Natalia, Runfola Timothy, Jones Tamara L, Mackiewicz Mark, Martin Scott E, Mushinski J Frederic, Stephens Robert, Caplen Natasha J
Gene Silencing Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Mol Cancer Res. 2008 Feb;6(2):212-21. doi: 10.1158/1541-7786.MCR-07-0105.
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.
PVT1基因座被确定为T(2;8)和T(8;22)“变异型”MYC激活染色体易位断点的簇集，在一部分（约20%）伯基特淋巴瘤（vBL）中，这些断点在MYC下游延伸400 kb。最近有报道称，微小RNA（miRNA）可能与脆性位点和癌症相关基因组区域有关，这促使我们研究8号染色体q24上的PVT1区域是否含有miRNA。对覆盖PVT1基因座的基因组序列进行计算分析并通过实验验证，确定了7种miRNA。其中一种miRNA，hsa-miR-1204，位于先前描述的PVT1外显子（1b）内，该外显子在vBL中常与免疫球蛋白轻链恒定区融合，并且在MYC/PVT1扩增的肿瘤中以高拷贝数存在。与其人类对应物一样，小鼠mmu-miR-1204是最接近Myc的miRNA（约50 kb），仅在一组逆转录病毒整合位点下游1至2 kb处发现。另一种miRNA，mmu-miR-1206，靠近与小鼠浆细胞瘤和小鼠Pvt1外显子1相关的变异易位断点簇集。实际上，与未成熟B细胞相比，几乎所有miRNA前体转录本在晚期B细胞（包括浆细胞瘤和vBL细胞系）中的表达水平都更高，这表明它们在淋巴细胞发育和/或淋巴瘤中可能发挥作用。此外，慢病毒载体介导的miR-1204前体（人类和小鼠）在小鼠前B细胞系中的过表达增加了Myc的表达。在几种MYC/PVT1共扩增的上皮癌细胞系中也观察到hsa-miR-1204前体的高水平表达，这表明这些miRNA在肿瘤发生中可能具有广泛的作用。
