GENOM IC ANALYSIS OF (1;7) TRANSLOCATION AND del(7q) IN MYELODYSPLASTIC SYNDROME

骨髓增生异常综合征 (1;7) 易位和 del(7q) 的基因组 IC 分析

• 批准号: 14570962
• 负责人: OGAWA Seishi
• 金额: $ 2.24万
• 依托单位: The UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570962/
• 关键词: t(1;7)(q10:910); del(7q); methylation analysis; myelodysplastic syndrome; alphoid sequences; CpG islands; Methylation pattern; MDS; CpGアイランド; der(1;7)(q10;p10); 欠失解析

The unbalanced translocation t(1;7)(q10;p10) and the del(7q) are recurrent chromosomal aberrations found in myelodysplastic syndrome (MDS) and predicts a very poor prognosis. Thus, o improve (heir treatment outcome, it is of particular importance to disclose the molecular pathogenesis of these critical abnormalities, which is our research goal. In (his study we performed genetic analyses of these translocation and deletion, in an attempt to identify the critical gene(s) involved in these aberrations. First, using quantitative FISH analysis using two centromere alphoid probe, DIZ7 and D7ZI from the centromere 1q chromosome I and 7, respectively, we revealed that these two alphoids are directly involved in t(1;7) translocation. Combined with other results, it is postulated that this translocation is generated as a result of misconnect between these. highly homologous alphoids during a recombinational repair process. It is also suggested that Trisomy 1q and monosomy 7q, rather than breakpoint genes are responsible to the pathogenesis. For the targets of del(7q), we performed an comprehensive methylation analysis of CpG islands on 7q, in which a total of 130 CpG islands (60% of all CpG islands on 7q) successfully amplified by bisulfite-PCR were examined for their aberrant methylation using direct sequencing for a number of hematopoietic tumor samples including MDS. Two genes were identified which exist down stream of highly and frequently methlated CpG islands and whose expression was down regulated in a methylation-dependent manner. These are though to be candidates of tumor suppressor genes that is relevant to pathogenesis of MDS with loss of 7q materials and a mutation analysis involving a large number of MDS samples is in progress.

不平衡易位 t(1;7)(q10;p10) 和 del(7q) 是骨髓增生异常综合征 (MDS) 中反复出现的染色体畸变，预示预后非常差。因此，为了改善治疗结果，揭示这些关键异常的分子发病机制尤为重要，这是我们的研究目标。在他的研究中，我们对这些易位和缺失进行了遗传分析，试图找出参与这些畸变的关键基因。首先，使用来自着丝粒 1q 的两个着丝粒 alphoid 探针 DIZ7 和 D7ZI 进行定量 FISH 分析 分别在 I 号染色体和 7 号染色体上，我们发现这两个 alphoid 直接参与 t(1;7) 易位。结合其他结果，推测这种易位是由于它们之间的错误连接而产生的。重组修复过程中高度同源的阿尔菲斯。还表明，三体 1q 和单体 7q，而不是断点基因负责发病机制。对于目标 del(7q)，我们对 7q 上的 CpG 岛进行了全面的甲基化分析，其中使用直接测序对包括 MDS 在内的许多造血肿瘤样本检查了通过亚硫酸氢盐-PCR 成功扩增的总共 130 个 CpG 岛（占 7q 上所有 CpG 岛的 60%）的异常甲基化。鉴定出两个基因存在于高度且频繁甲基化的下游 CpG 岛，其表达以甲基化依赖性方式下调。这些被认为是与7q材料丢失的MDS发病机制相关的候选肿瘤抑制基因，并且涉及大量MDS样本的突变分析正在进行中。

项目成果

Saito A, Ogawa S, et al.: "Establishment of a quantitative method for detecting mixed chimerism using fluorescence-based PCR amplification of short tandem repeat markers after allogeneic hematopoietic stem cell transplantation in a Japanese population"Jap

Saito A、Okawa S 等人：“在日本人群中进行同种异体造血干细胞移植后，使用基于荧光的 PCR 扩增短串联重复标记物来检测混合嵌合现象的定量方法”

Wang L, Ogawa S, Hangaishi A, Qiao Y, Hosoya N, Nanya Y, Ohyashiki K, Mizoguchi H, Hiral H.: "Molecular characterization of the recurrent unbalanced translocation der(1;7)(q10;p10)."Blood. 102. 2597-2604 (2003)

Wang L, Okawa S, Hangaishi A, Qiao Y, Hosoya N, Nanya Y, Ohyashiki K, Mizoguchi H, Hiral H.：“周期性不平衡易位 der(1;7)(q10;p10) 的分子特征。”血液

Ogawa S, Hangaishi A, Hirai, H: "Identification of candidate tumor suppressor genes from critical deletions of long arm of chromosome 6 in hematopoietic neoplasm."Inyernational Congress Series. 1246. 251-260 (2002)

Okawa S、Hangaishi A、Hirai、H：“从造血肿瘤中 6 号染色体长臂的关键缺失中鉴定候选肿瘤抑制基因。”国际国会系列。

Ichikawa M, Asai T, Saito T, Yarnamoto G, Seo S, Yarnazaki I, Yamagata T, Mitani K, Chiba S, Hirai H, Ogawa S, Kurokawa M.: "AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopojetic stem cel

Ichikawa M、Asai T、Saito T、Yarnamoto G、Seo S、Yarnazaki I、Yamagata T、Mitani K、Chiba S、Hirai H、Okawa S、Kurokawa M.：“AML-1 是巨核细胞成熟和淋巴细胞分化所必需的，

Hosoya N, Ogawa S, et al.: "Molecular cytogenetic analyses of HIG, a novel human cell line carrying t(1;3)(p36.3;q25.3) established from a patient with chronic myelogenous leukemia in blastic crisis."Int J Hematol. 78. 432-438 (2003)

Hosoya N、Okawa S 等人：“HIG 的分子细胞遗传学分析，HIG 是一种携带 t(1;3)(p36.3;q25.3) 的新型人类细胞系，由患有急变期慢性粒细胞白血病的患者建立。