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Development of the optimal therapies based on molecular genetics of multiple myeloma

基于多发性骨髓瘤分子遗传学的最佳疗法的开发

基本信息

批准号：
12470202
负责人：
UEDA Ryuzo
金额：
$ 7.74万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

1.Identification of novel chromosomal translocations found in multiple myeloma :1)t(1;14)(p34;q32) : 1p34 breakpoint of ODA cells was isolated by genomic cloning and found to have disrupted E3/LAPTm5 gene in terms of its expression. This phenomenon was caused by hypermethylation of the regulatory sequences of the gene.2)t(1;14)(p34;q32) : 1p34 breakpoint of ODA cells was isolated by genomic cloning and found to have disrupted E3/LAPTm5 gene in the first intron. Interestingly, this gene was shut off in 60% of the myeloma cell lines in terms of its expression. This phenomenon was caused by hypermethylation of the regulatory sequences of the gene.2.14q32 translocations in MGUS/smoldering multiple myeloma(SMM)Purified plasma cells derived from 16 MGUS/SMM patients were examined concerning 14q32 chromosomal trans locations by means of double color-FISH analysis. 56% of the cases carried 14q32 translocations, in which two thirds were between 14q32(IgH) and 11q13(CCND1) loci with concomitant nuclear expression of CyclinD1.3.Identification of the distinct developmental pathways of multiple myeloma :Quantitative RT-PCR assay was established for CCND1, FGFR3, MUM1, c-MAF, MAFB and c-MYC genes, and applied for the study of 19 cell lines and 30 myeloma samples. It led to the identification of at least three distinct developmental pathways of multiple myeloma, which originated from altered expression of CCND1, FGFR3 and c-MAF/MAFB genes.

1.多发性骨髓瘤中发现的新染色体易位的鉴定：1）通过基因组克隆分离ODA细胞的t（1;14）（p34;q32）：1 p34断裂点，发现E3/LAPTm 5基因在其表达方面被破坏。2）t（1;14）（p34;q32）：1 p34断裂点的基因组克隆，发现E3/LAPTm 5基因第一内含子被破坏。有趣的是，就其表达而言，该基因在60%的骨髓瘤细胞系中被关闭。这种现象是由基因调节序列的高甲基化引起的。2.MGUS/闷烧多发性骨髓瘤（SMM）中的14 q32易位通过双色-FISH分析检查了来自16名MGUS/SMM患者的纯化浆细胞的14 q32染色体易位。56%的病例存在14 q32易位，其中2/3的病例位于14 q32（IgH）和11 q13（CCND 1）之间，并伴有CyclinD 1的核表达。3.多发性骨髓瘤不同发生途径的鉴定：建立了CCND 1、FGFR 3、MUM 1、c-MAF、MAFB和c-MYC基因的定量RT-PCR方法，并应用于19个细胞系和30个骨髓瘤标本的研究。它导致了多发性骨髓瘤的至少三种不同的发展途径的鉴定，其起源于CCND 1，FGFR 3和c-MAF/MAFB基因的表达改变。