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

染色体易位涉及免疫球蛋白重链（IGH）基因在带14q32.3和它的伙伴基因的发病机制和B细胞恶性肿瘤的临床特征。为了明确14q32.3易位与特定癌基因位点的发生率，我们分析了113例MM患者的双色荧光原位杂交（DC-FISH）。使用IGH基因（14q32.3）与c-MYC（8q24.1）、CCND 1（11q13.3）、FGFR 3（4p 15）、MUM 1/IRF 4（6p 25）和BCL 2（18 q21）基因探针的组合，在105名通过DC-FISH评估的患者中的69名（66%）中检测到IGH易位。染色体t（11 ;在38名患者中的27名（71%）中检测到t（8 ; 14）作为CCND 1与IGH探针的融合信号;在35名患者中的11名（31%）中检测到t（8 ; 14）作为c-MYC与IGH的融合;并且在38名患者中的8名（21%）中检测到t（6 ; 14）作为MUM 1与IGH的融合。IGH双易位9例（21%）. CCND 1/IGH重排与MM的浆细胞白血病或白血病表现有关。 ...更多信息 与侵袭性疾病相关。FGFR 3/IGH重排患者常出现溶骨性病变，根据其表面免疫表型可分为前B细胞（CD 38+，CD 19-）、未成熟浆细胞（CD 38+，CD 19-，MPC-）和成熟浆细胞（CD 38+，CD 19-，MPC+）。在所有15例分析的患者中，前B细胞均未参与IGH易位。我们根据携带IGH易位的细胞群体定义了三种不同的模式：未成熟（-）和成熟（+），未成熟（+）和成熟（+），以及未成熟（-f）和成熟（-）。FGFR阳性患者表现出所有三种模式，而c-MYC或CCND 1阳性患者未表现出不成熟（+）/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FGFR 3/IGH易位在骨髓瘤发生过程中既作为原发事件也作为附加事件发生。此外，c-MYC/IGH或FGFR 3/IGH易位的获得可能与疾病的进展相关。少

项目成果

Nomura K: "Differentiation of follicular from mucosa-associated lymphoid tissue lymphoma by detection of t(14;1 8) on single cell preparatbns and paraffin-embedded sections"Genes Chromosomes Cancer. 33(2). 213-216 (2002)

Nomura K：“通过检测单细胞制剂和石蜡包埋切片上的 t(14;1 8) 来区分滤泡与粘膜相关淋巴组织淋巴瘤”基因染色体癌症。

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。

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。

Inokuchi K: "Establishment of a cell line with AML1-MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia"Genes Chromosomes Cancer. 32(2). 182-187 (2001)

Inokuchi K：“急性髓性白血病中 AML1-MTG8、TP53 和 TP73 异常的细胞系的建立”基因染色体癌症。

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。