Study of hematopoietic tumor disease genes using mouse models

利用小鼠模型研究造血肿瘤疾病基因

• 批准号: 12213140
• 负责人: NAKAMURA Takuro
• 金额: $ 54.34万
• 依托单位: Japanese Foundation for Cancer Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213140/
• 关键词: Evi9; Bcllla; Ritl; Bclllb; BXH2; myeloid leukemia; thymic lymphoma; NUP98-HOXA9; Meisl; retroviral insertional mutaenesis; アポトーシス; BHX2; BHX2マウス; BXH-2マウス; 転写調節; 分化

We engaged in the current study using retrovirus-and radiation-induced mouse hematopoietic tumor models. The major genes of subject in each model were Evi9/Bcl11a and Rit1/Bcl11b, both of which belong to the Bcl11 gene family and play an important role in the development of B-cell and T-cell, respectively. Evi9/Bcl11a is a human B-cell oncogene and a murine myeloid oncogene. We have revealed that Bcl11a is essential for B-cell development using a Bcl11a knockout model and the Bcl11a activity for B-cell development might be related to its transcriptional regulatory activity on the immunoglobulin heavy chain enhancer with E2A. It was also shown that Bcl11a plays an important role in T-cell development. To the contrary, Rit1/Bcl11b has been identified as a tumor suppressor in mouse thymic lymphoma. Analysis of the Bcl11b knockout mouse revealed that Bcl11b is essential for T-cell development and loss of Bcl11b results in apoptosis of T-cells. There was significantly higher incidence of th … More ymic lymphoma in Bcl11b -/+ mice than in wild type littermates by □-irradiation. Approximately 50% of lymphoma showed loss of the wild type allele of Bcl11b. Moreover, Bcl11b -/+ and p53 -/+ double heterozygous mice frequently developed thymic lymphoma by 300 day of age without irradiation. Decrease of the Bcl11 protein induced apoptosis by downregulating the anti-apoptotic protein BclxL, cell cycle arrest at the S phase and inhibition of Chk1 phosphorylation. These results suggest that Bcl11b may interact with Chk1 and acts in genome stabilization funcion. Analyzing transgenic mice, it was shown that NUP98-HOXA9 induces G-CSF hypersensitivity of myeloid progenitors. Meis1 and novel 5 genes were identified as cooperative genes for NUP98-HOXA9 in leukemogenesis by using retroviral insertional mutagenesis. Among these genes Fcgr2b was found involved in human hematological malignancies, indicating that the model is important to understand molecular mechanisms of human leukemogenesis. Furthermore, MAPK signaling molecules and Mel1 were identified as candidate cooperative genes for NUP98-HOXA9 and HOX co-factors. Less

我们使用逆转录病毒和辐射诱导的小鼠造血肿瘤模型进行了当前的研究。每个模型中受试者的主要基因是Evi9/Bcl11a和Rit1/Bcl11b，两者都属于Bcl11基因家族，分别在B细胞和T细胞的发育中发挥重要作用。 Evi9/Bcl11a 是人类 B 细胞癌基因和鼠骨髓癌基因。我们使用 Bcl11a 敲除模型揭示了 Bcl11a 对于 B 细胞发育至关重要，并且 Bcl11a 对 B 细胞发育的活性可能与其 E2A 对免疫球蛋白重链增强子的转录调节活性有关。研究还表明，Bcl11a 在 T 细胞发育中发挥着重要作用。相反，Rit1/Bcl11b 已被确定为小鼠胸腺淋巴瘤的肿瘤抑制因子。对 Bcl11b 敲除小鼠的分析表明，Bcl11b 对于 T 细胞发育至关重要，Bcl11b 缺失会导致 T 细胞凋亡。通过□-照射，Bcl11b -/+ 小鼠的胸腺淋巴瘤发病率明显高于野生型同窝小鼠。大约 50% 的淋巴瘤显示 Bcl11b 野生型等位基因缺失。此外，Bcl11b -/+ 和 p53 -/+ 双杂合小鼠在未接受辐射的情况下，在 300 日龄时经常出现胸腺淋巴瘤。 Bcl11 蛋白的减少通过下调抗凋亡蛋白 BclxL、细胞周期停滞在 S 期和抑制 Chk1 磷酸化来诱导细胞凋亡。这些结果表明 Bcl11b 可能与 Chk1 相互作用并发挥基因组稳定功能。分析转基因小鼠后发现，NUP98-HOXA9 会诱导骨髓祖细胞的 G-CSF 超敏反应。通过使用逆转录病毒插入诱变，Meis1 和新颖的 5 基因被鉴定为 NUP98-HOXA9 在白血病发生中的协同基因。在这些基因中，Fcgr2b被发现与人类血液恶性肿瘤有关，表明该模型对于理解人类白血病发生的分子机制具有重要意义。此外，MAPK信号分子和Mel1被确定为NUP98-HOXA9和HOX辅因子的候选协同基因。较少的

项目成果

p53 prevents maturation to the immature CD4^-CD8^+stage of T cell development in Bcl11b-/-mice.

p53 阻止 Bcl11b-/- 小鼠 T 细胞发育成熟至未成熟的 CD4^-CD8^ 阶段。

• 发表时间: 2005
• 期刊: Biochemical and Biophysical Research Communication 328(2)
• 作者: Nagahata;T.;Onda;M.;Emi;M.;Nagai;H.;Tsumagari;K.;Fujimoto;T.;Hirano;A.;Sato;T.;Nishikawa;K.;Akiyama;F.;Sakamoto;G.;Kasumi;F.;Miki.Y..Tanaka;T.;Tsunoda;T.;Okazuka K et al.
• 通讯作者: Okazuka K et al.

Bcl11a signaling is essential for B- and T-cell development

Bcl11a 信号传导对于 B 细胞和 T 细胞发育至关重要

• 发表时间: 2003
• 期刊: Nature Immunology 6
• 作者: Nagahata;T. et al.;Liu et al.
• 通讯作者: Liu et al.

Genetic loci controlling susceptibility to gamma-ray induced thymiclymphoma.

控制对伽马射线诱导的胸腺淋巴瘤易感性的遗传位点。

• 发表时间: 2001
• 期刊: Oncogene 20
• 作者: Saito Y;Ochiai Y;Kodama Y;Tamura Y;Togashi T;Kosugi・Okano H;Miyazawa T;Wakabayashi Y;Hatakeyama K;Wakana S;Niwa O;Kominami R.
• 通讯作者: Kominami R.

Ochiai Y: "Mapping of genetic modifiers of thymic lymphoma development in p53-knockout mice"Oncogene. (印刷中). (2003)

Ochiai Y：“p53 敲除小鼠胸腺淋巴瘤发展的遗传修饰物的图谱”Oncogene（出版中）。

Suzuki A: "t(7;11)(p15;p15) chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion"Br J Haematol. 116・1. 170-172 (2002)

Suzuki A：“t(7;11)(p15;p15) 慢性粒细胞白血病发展为原始细胞转化，显示出新型 NUP98/HOXA11 融合”Br J Haematol. 116·1 (2002)。