Molecular studies of IG translocation and PVT1 and DCC gene rearrangements in multiple myeloma

为了阐明多发性骨髓瘤（MM）的病理生理学，我们使用FISH、SKY、寡核苷酸阵列和RT-PCR方法对染色体8 q24和18 q21重排处的断点进行了分子解剖。在54例MM患者中的7例（13.0%）和11例MM细胞系中的5例（45.5%）中检测到PVT 1重排。鉴定了两个新的嵌合基因，PVT 1-Nepsin和PVT 1-WWOX。PVT 1外显子1与Nmix外显子2融合的PVT 1-Nmix嵌合体和PVT 1外显子1与WWOX外显子9融合的PVT 1-WWOX嵌合体分别与Nmix异常表达和N端缺失的WWOX表达相关，提示PVT 1重排可能代表了8 q24重排阳性多发性骨髓瘤病理学的一种新的分子模式。另一方面，我们的研究集中在18 q21确定异常DCC转录，其中DCC外显子2融合到DCC内含子1的一部分，因此缺乏外显子1在15个细胞系中使用气泡PCR的cDNA。DCC蛋白N端缺失，提示DCC结构异常在MM的发生发展中起一定作用。

To elucidate pathophysiology of multiple myeloma (MM), we performed molecular dissection of the breakpoints at chromosomal 8q24 and 18q21 rearrangements using FISH, SKY, oligonucleotide array , and RT -PCR procedures. PVT1 rearrangements were detected in 7 (13.0%) of 54 MM patients and 5 (45.5 %) of 11 MM cell lines. Two novel chimeric genes were identified, PVT1-NBEA and PVT1-WWOX. 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. On the other hand, our studies focusing on 18q21 identified abnormal DCC transcripts in which DCC exon 2 was fused to part of DCC intron 1 hence lacking exon 1 in 15 cell lines using bubble PCR for cDNA. Putative abnormal DCC protein lacks a part of N-terminus, suggesting that structural abnormalities of DCC play some roles in the development and progression of MM.