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Genomic alteration in hematologic malignancies and their roles for proliferation and differentiation

血液恶性肿瘤中的基因组改变及其对增殖和分化的作用

基本信息

批准号：
16390282
负责人：
SETO Masao
金额：
$ 9.15万
依托单位：
Aichi Cancer Center
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390282/
关键词：
MALT lymphoma API2-MALT1 Mantle cell lymphoma DLBCL Array CGH Genome alteration Lymphoma Chromosome translacation MALTリンパ腫アレイCGH ゲノム

项目摘要

1.MALT lymphoma related genes for cell differentiation and proliferation :MALT1, BCL10 (B-cell lymphoma 10), and API2 (apoptosis inhibitor 2)-MALT1 are key molecules in mucosa-associated lymphoid tissue (MALT) lymphomagenesis. We previously reported that MALT1 and API2- MALT1 were localized only in cytoplasm, where we suggested that both molecules were likely to be active. We examined the localization-determining region by generating various mutants and were able to demonstrate that there were nuclear export signal (NES)-containing domains in the MALT1 C-terminal region. The use of leptomycin B, an NES-specific inhibitor, demonstrated that both MALT1 and API2- MALT1 were predominantly retained in the nuclei, indicating that these molecules were shuttling between nucleus and cytoplasm in an NES-dependent manner.2.Genomic alterations in malignant lymphoma :Diffuse large B-cell lymphoma (DLBCL) comprises molecularly distinct subgroups such as activated B- cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL. We previously reported that CD5+ and CD5-CD10+DLBCL constitute clinically relevant subgroups. To determine whether these two subgroups are related to ABC and GCB DLBCL, we analyzed the genomic imbalance of 99 cases using array-CGH. 46 of these cases were subsequently subjected to gene expression profiling. A comparison of genome profiles of distinct subgroups of DLBCL demonstrated specific genomic alterations to each subtype. We have also analyzed Mantle cell lymphoma (MCL) with array CGH technology and found MCL specific genomic alterations. In MCL 2q13 homologous deletion was found in addition to recurrent heterozygous losses. The target gene was found to be BIM1, an antagonist of BCL2, suggesting a role for MCL lymphomagenesis.

1. MALT淋巴瘤细胞分化和增殖相关基因：MALT 1、BCL 10（B细胞淋巴瘤10）和API 2（凋亡抑制剂2）-MALT 1是粘膜相关淋巴组织（MALT）淋巴瘤发生中的关键分子。我们以前报道过MALT 1和API 2-MALT 1仅定位于细胞质中，我们认为这两种分子可能都有活性。我们通过产生各种突变体来检查定位决定区，并且能够证明在MALT 1 C-末端区域中存在含有核输出信号（内斯）的结构域。NES特异性抑制剂来普霉素B的应用表明，MALT 1和API 2-MALT 1主要保留在细胞核中，表明这些分子以NES依赖的方式穿梭于细胞核和细胞质之间。2.恶性淋巴瘤的基因组改变：弥漫性大B细胞淋巴瘤（DLBCL）包括分子上不同的亚类，如活化B细胞样（ABC）和生发中心B细胞样（GCB）DLBCL。我们以前报道过，CD 5+和CD 5-CD 10 +DLBCL构成临床相关亚组。为了确定这两个亚组是否与ABC和GCB DLBCL相关，我们使用阵列CGH分析了99例病例的基因组失衡。其中46例随后进行了基因表达谱分析。DLBCL的不同亚组的基因组谱的比较显示了每个亚型的特异性基因组改变。我们还分析了套细胞淋巴瘤（MCL）与阵列CGH技术，发现MCL特异性基因组改变。在MCL 2 q13同源性缺失被发现除了经常性杂合损失。发现靶基因是BIM 1，BCL 2的拮抗剂，表明MCL淋巴瘤发生的作用。