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，我们使用FISH、SKY、寡核苷酸阵列和RT -PCR方法对染色体8q24和18q21重排的断点进行了分子解剖。54例MM患者中有7例（13.0%）和11例MM细胞系中有5例（45.5%）检测到PVT1重排。鉴定出两个新的嵌合基因PVT1-NBEA和PVT1-WWOX。PVT1外显子1与NBEA外显子2融合的PVT1-NBEA嵌合体和PVT1外显子1与WWOX外显子9融合的PVT1-WWOX嵌合体分别与异常NBEA和缺n端WWOX的表达相关。这些发现表明，PVT1重排可能代表了8q24重排阳性多发性骨髓瘤病理的一种新的分子范式。另一方面，我们对18q21的研究在15个细胞系中发现了DCC异常转录本，其中DCC外显子2与部分DCC内含子1融合，因此缺乏外显子1。推测异常DCC蛋白缺少部分n端，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.