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：MALT1、BCL10（B细胞淋巴瘤10）和API2（凋亡抑制剂2）-MALT1是粘膜相关淋巴组织（MALT）淋巴瘤发生的关键分子。我们之前报道过 MALT1 和 API2-MALT1 仅位于细胞质中，我们认为这两种分子可能都具有活性。我们通过生成各种突变体来检查定位决定区域，并能够证明 MALT1 C 末端区域存在包含核输出信号 (NES) 的结构域。使用NES特异性抑制剂leptomycin B，证明MALT1和API2-MALT1主要保留在细胞核中，表明这些分子以NES依赖性方式在细胞核和细胞质之间穿梭。 2.恶性肿瘤中的基因组改变淋巴瘤：弥漫性大 B 细胞淋巴瘤 (DLBCL) 包含分子上不同的亚组，例如活化 B 细胞样 (ABC) 和生发中心 B 细胞样 (GCB)弥漫大B细胞淋巴瘤。我们之前报道过 CD5+ 和 CD5-CD10+ 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 array-CGH 分析了 99 例病例的基因组失衡。随后对其中 46 个病例进行了基因表达谱分析。对 DLBCL 不同亚组的基因组图谱的比较证明了每个亚型的特定基因组改变。我们还利用阵列 CGH 技术分析了套细胞淋巴瘤 (MCL)，发现了 MCL 特异性基因组改变。在 MCL 2q13 中，除了反复出现的杂合性缺失外，还发现了同源缺失。目标基因被发现是 BIM1（BCL2 的拮抗剂），表明其在 MCL 淋巴瘤发生中发挥作用。