Exploring leukemogenic mechanism using genomic analysis and mouse genetics.

利用基因组分析和小鼠遗传学探索白血病发生机制。

• 批准号: 16390272
• 负责人: OGAWA Seishi
• 金额: $ 9.22万
• 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 (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-16390272/
• 关键词: Leukemia; Copy number analysis; SNP array; CNAG; Allele-specific analysis; UPD; LOH; マイクロアレイ; Blimp1; 細胞周期; モデルマウス; Affymetrix

Leukemia is a neoplastic state in which deregulated cell division, differentiaion, and apoptosis lead to unregulated clonal proliferation of hematopoietic progenitors and the molecular basis for these abnormalities should be finally ascribed to the genetic alterations in leukemia genome. Thus the identification of those genetic changes is of crucial importance for the understanding of leukemogeneic mechanism. The purpose of this study is exploring leukemia genomes for genetic abnormalities using advanced microarray technologies, identifying their molecular targets and clarifying the leukemogenic mechanism through analysis of the target molecules using mouse genetics. In this study, we newly developed a robust system for copy number detection of cancer genome using high-density oligonucleotide microarrays (CNAG) and comprehensively analyzed copy number alterations in leukemia genomes. We analyzed a total of 886 leukemia samples and found numerous copy number abnormalities, including those that are commonly involved in multiple samples. Due to the extremely high resolution, the candidate gene that might be relevant to leukemogenesis was uniquely identified for many abnormal regions. Blimp1 is one of such target found in a homozygous deletion at 6q21 in ATL. Interestingly, conditional Blimp1 targeted mice show lymphonode swelling as well as splenomegaly. In addition, we revealed that it is mutated in primary ATL samples and when expressed in Hela cells, induces cell arrest at both G1 and G2 phases, indicating its tumor suppressive function.

白血病是一种细胞分裂、分化和凋亡失调导致造血祖细胞克隆性增殖失调的肿瘤状态，这些异常的分子基础最终应归因于白血病基因组的遗传改变。因此，这些遗传学改变的鉴定对于理解白血病发生机制至关重要。本研究的目的是利用先进的微阵列技术探索白血病基因组中的遗传异常，确定其分子靶点，并通过利用小鼠遗传学分析靶分子来阐明白血病的发生机制。在这项研究中，我们新开发了一个强大的系统，用于使用高密度寡核苷酸微阵列（CNAG）检测癌症基因组的拷贝数，并全面分析了白血病基因组的拷贝数变化。我们分析了总共886个白血病样本，发现了许多拷贝数异常，包括那些通常涉及多个样本。由于极高的分辨率，可能与白血病发生相关的候选基因在许多异常区域被唯一地鉴定。Blimp1是在ATL的6q21纯合缺失中发现的这样的靶标之一。有趣的是，条件性Blimp1靶向小鼠显示淋巴结肿胀以及脾肿大。此外，我们发现它在原代ATL样品中发生突变，当在Hela细胞中表达时，诱导细胞停滞在G1和G2期，表明其肿瘤抑制功能。

项目成果

Functional Domains of Runx1 Are Differentially Required for CD4 Repression, TCR{beta} Expression, CD4/8 Double-Negative to CD4/8 Double-Positive Transition in Thymocyte Development.

胸腺细胞发育中 CD4 抑制、TCR{β} 表达、CD4/8 双阴性到 CD4/8 双阳性转变所需的 Runx1 功能域存在差异。

• 发表时间: 2005
• 期刊: J.Immunol. 174
• 作者: Kawazu M;Asai T;Ichikawa M;Yamamoto G;Saito T;Goyama S;Mitani K;Miyazono K;Chiba S;Ogawa S;Kurokawa M;Hirai H.
• 通讯作者: Hirai H.

Hematopoietic stem cells expanded by fibroblast growth factor-1 are excellent targets for retrovirus-mediated gene delivery

• DOI: 10.1016/j.exphem.2005.09.001
• 发表时间: 2005-12-01
• 期刊: EXPERIMENTAL HEMATOLOGY
• 影响因子: 2.6
• 作者: Crcareva, A;Saito, T;Chiba, S
• 通讯作者: Chiba, S

Educational Program Book : Japanese Society of Hematology and Japanese Society of Clinical Hematology.

教育计划书：日本血液学会和日本临床血液学会。

• 发表时间: 2004
• 作者: Goyama S;Ogawa S;et al.;Ogawa S
• 通讯作者: Ogawa S

The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonic para-aortic splanchnopleural(P-Sp)region.

AML1 的转录活性形式是 AML1 缺陷的胚胎主动脉旁内脏胸膜 (P-Sp) 区域的造血拯救所必需的。

• 发表时间: 2004
• 期刊: Blood 104
• 作者: Goyama;S.
• 通讯作者: S.

AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues

• DOI: 10.1074/jbc.m400355200
• 发表时间: 2004-04-09
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Yamaguchi, Y;Kurokawa, M;Hirai, H
• 通讯作者: Hirai, H