SUBCLASSFICIATION OF MULTIPLE MYELOMA BASED ON THE PARTNER GENES OF TUMOR-SPECIFIC IMMUNOGLOBULIN HEAVY CHAIN GENE TRANSLOCATION BY USING DOUBLE-COLOR FLUORESCENCE IN SITU HYBRIDIZATION

双色荧光原位杂交基于肿瘤特异性免疫球蛋白重链基因易位伴侣基因的多发性骨髓瘤亚分类

• 批准号: 12671001
• 负责人: TANIWAKI Masafumi
• 金额: $ 1.98万
• 依托单位: KYOTO PREFECTURAL UNIVERSITY OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671001/
• 关键词: myeloma; conogene; IGH gene; FISH; diagnosis; chromosome; 蛍光in situ分子雑種法; 多発性骨髄種

Chromosomal translocation involving the immunoglobulin heavy chain (IGH) gene at band 14q32.3 and its partner genes are implicated in both the pathogenesis and clinical characteristics of B-cell malignancies. To define the incidence of 14q32.3 translocation with specific oncogene loci, we analyzed 113 patients with MM by double-color fluorescence in situ hybridization (DC-FISH). Using the IGH gene (14q32.3) in combination with c-MYC (8q24.1), CCND1 (11q13.3), FGFR3 (4p15), MUM1/IRF4(6p25), and BCL2 (18q21) gene probes detected IGH translocations in 69 (66 %) of 105 patients who were assessed by DC-FISH. Chromosome t(11 ; 14) was detected in 27 (71 %) of 38 patients as fusion signal of CCND1 with IGH probes; t(8 ; 14) in 11 (31 %) of 35 as fusion of c-MYC with IGH ; and t(6 ; 14) in 8 (21 %) of 38 as MUM1 with IGH. Double IGH translocation was detected 9 (21 %) of 43 patients. CCND1/IGH rearrangement was associated with plasma cell leukemia or leukemia manifestation of MM. C-MYC/IGH rea … More rrangement was associated with aggressive disease. Lytic bone lesion was frequently found in patients with FGFR3/IGH rearrangement.Three distinct cell populations were defined based on the surface immunophenotype ; pre-B cell (CD38+, CD19-), immature plasma cell (CD38+, CD19-, MPC-), and mature plasma cell (CD38+, CD19-, MPC+). Pre-B cells were not involved in IGH translocation in all 1 5 patients analyzed. We defined three distinct patterns based on cell populations carrying IGH translocation; immature(-) and mature(+), immature(+) and mature(+) , and immature(-f) and mature(-). FGFRS-positive patients demonstrated all three patterns, whereas c-MYC- or CCND1-positive patients did not showed immature(+)/mature(-) pattern. The present studies suggest that single IGH translocation can transform normal cells to myeloma cells and that FGFR3/IGH translocation occurs as both primary and additional event during the myelomagenesis. Furthermore, acquisition of c-MYC/IGH or FGFR3/IGH translocation may be associated with progression of the diseases. Less

涉及Band 14Q32.3的免疫球蛋白重链（IGH）基因及其伴侣基因的染色体易位植入了B细胞恶性肿瘤的发病机理和临床特征。为了用特定的癌基因局部定义14q32.3易位的发生率，我们通过双色荧光原位杂交（DC-FISH）分析了113例MM患者。使用IGH基因（14q32.3）与C-MYC（8Q24.1），CCND1（11Q13.3），FGFR3（4P15），MUM1/IRF4（6P25）和BCL2（6p25）和BCL2（18Q21）基因问题在69％（66％）中被评估了105患者的IGH转运。在38例患者中，有27名（71％）在IGH探针中检测到27例CCND1融合信号中的27例（71％）染色体T（11; 14）。 t（8; 14）在35个中的11（31％）中为c-myc与igh的融合；和t（6; 14）在38中的8（21％）中为MUM1，带有IGH。在43名患者中，检测到9（21％）的双重易位。 CCND1/IGH重排与MM的血浆细胞白血病或白血病相关。 c-myc/igh rea…更多的rangement与侵略性疾病有关。在FGFR3/IGH重排患者中经常发现裂解骨病变。在所有15例分析的1例患者中，三个不同的细胞前B细胞均未参与IGH易位。我们根据带有IGH易位的细胞群来定义三种不同的模式。未成熟（ - ）和成熟（+），未成熟（+）和成熟（+）以及未成熟（-f）和成熟（ - ）。 FGFRS阳性患者证明了所有三种模式，而C-MYC或CCND1阳性患者没有显示未成熟（+）/成熟（ - ）模式。目前的研究表明，单个IGH易位可以将正常细胞转化为骨髓瘤细胞，并且在骨髓造成期间，FGFR3/IGH易位是主要事件和其他事件。此外，c-myc/igh或fgfr3/igh易位的获取可能与疾病的进展有关。较少的

项目成果

谷脇雅史: "血球におけるin situ分子雑種法の応用-間期核と細胞レベルの染色体遺伝子解析特集「血球を見る」時代から「血球で考える」時代へ"血液フロンテイア. 10・5. 75-81 (2000)

谷胁正史：《原位分子杂交方法在血细胞中的应用——间期核与细胞水平染色体遗传分析特刊从‘看血细胞’时代到‘用血细胞思考’时代》《血液前沿》 10・5。75-81（2000）

Mochizuki N: "A novel gene, MEL1, mapped to 1 p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3) (p36;q21)-positive leukemia cells"Blood. 96(9). 3209-3214 (2000)

Mochizuki N：“映射到 1 p36.3 的一种新基因 MEL1 与 MDS1/EVI1 基因高度同源，并且在 t(1;3) (p36;q21) 阳性白血病细胞中转录激活”血液。

Kita-Sasai Y: "International prognostic scoring system (IPSS) and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome"Brit J Haematol. 115(2). 309-312 (2001)

Kita-Sasai Y：“国际预后评分系统（IPSS）和 TP53 突变是骨髓增生异常综合征患者的独立预后指标”Brit J Haematol。

Tatsumi K. et al.: "The CDCREL1 gene fused to MIL in de novo acute myeloid leukemia with t(11 ; 22)(q23 ; q11.2) and its frequent expression in myeloid leukemia cell lines"Genes Chromosomes Cancer. 30(3). 230-235 (2001)

Tatsumi K. 等人：“CDCREL1 基因在 t(11 ; 22)(q23 ; q11.2) 的新发急性髓系白血病中与 MIL 融合，及其在髓系白血病细胞系中的频繁表达”Genes Chromosomes Cancer。

Yagasaki F: "Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation"Cancer Res. 61(23). 8371-8374 (2001)

Yagasaki F：“外周 T 细胞淋巴瘤中 ETV6 与成纤维细胞生长因子受体 3 的融合，伴有 t(4;12)(p16;p13) 染色体易位”Cancer Res。