Department of Hematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
Cancer Res. 2012 Oct 1;72(19):4954-62. doi: 10.1158/0008-5472.CAN-12-0213. Epub 2012 Aug 6.
Chromosome 8q24 rearrangements are occasionally found in multiple myeloma and are associated with tumor progression. The 8q24 rearrangements were detected by FISH in 12 of 54 patients with multiple myeloma (22.2%) and in 8 of 11 multiple myeloma cell lines (72.7%). The breakpoints of 8q24 in 10 patients with multiple myeloma and in all multiple myeloma cell lines were assigned to a 360 kb segment, which was divided into 4 regions: approximately 120 kb centromeric to MYC (5' side of MYC), the region centromerically adjacent to PVT1 (~ 170 kb region, including MYC, of 5' side of PVT1), the PVT1 region, and the telomeric region to PVT1. PVT1 rearrangements were most common and found in 7 of 12 patients (58.3%) and 5 of 8 cell lines (62.5%) with 8q24 abnormalities. A combination of spectral karyotyping (SKY), FISH, and oligonucleotide array identified several partner loci of PVT1 rearrangements, such as 4p16, 4q13, 13q13, 14q32, and 16q23-24. Two novel chimeric genes were identified: PVT1-NBEA in the AMU-MM1 cell line harboring t(8;13)(q24;q13) and PVT1-WWOX in RPMI8226 cell line harboring der(16)t(16;22)ins(16;8)(q23;q24). The PVT1-NBEA chimera in which PVT1 exon 1 was fused to NBEA exon 2 and the PVT1-WWOX in which PVT1 exon 1 was fused to WWOX exon 9 were associated with the expression of abnormal NBEA and WWOX lacking their N-terminus, respectively. These findings suggest that PVT1 rearrangements may represent a novel molecular paradigm underlying the pathology of 8q24 rearrangement-positive multiple myeloma.
8q24 染色体重排偶尔在多发性骨髓瘤中发现，并与肿瘤进展相关。FISH 在 54 例多发性骨髓瘤患者中的 12 例（22.2%）和 11 例多发性骨髓瘤细胞系中的 8 例（72.7%）中检测到 8q24 重排。10 例多发性骨髓瘤患者和所有多发性骨髓瘤细胞系的 8q24 断点被分配到一个 360 kb 的片段，该片段分为 4 个区域：靠近 MYC 的着丝粒侧约 120 kb（MYC 的 5' 端），靠近 PVT1 的着丝粒侧区域（~170 kb 区域，包括 PVT1 的 5' 端的 MYC），PVT1 区域和 PVT1 端粒侧区域。PVT1 重排在 12 例患者中有 7 例（58.3%）和 8 例细胞系中有 5 例（62.5%）中最为常见，这些患者和细胞系中存在 8q24 异常。通过光谱核型分析（SKY）、FISH 和寡核苷酸阵列鉴定了 PVT1 重排的几个伙伴基因座，如 4p16、4q13、13q13、14q32 和 16q23-24。鉴定出两种新的嵌合基因：AMU-MM1 细胞系中携带 t(8;13)(q24;q13)的 PVT1-NBEA 和 RPMI8226 细胞系中携带 der(16)t(16;22)ins(16;8)(q23;q24)的 PVT1-WWOX。PVT1-NBEA 嵌合体中 PVT1 外显子 1 融合到 NBEA 外显子 2，而 PVT1-WWOX 嵌合体中 PVT1 外显子 1 融合到 WWOX 外显子 9，分别与异常 NBEA 和缺失其 N 端的 WWOX 的表达相关。这些发现表明，PVT1 重排可能代表 8q24 重排阳性多发性骨髓瘤病理的一种新的分子范例。
