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

我们目前使用逆转录病毒和辐射诱导的小鼠造血肿瘤模型进行研究，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基因家族并在造血肿瘤中发挥重要作用。 B 细胞和 T 细胞的发育分别是人类 B 细胞癌基因和鼠骨髓癌基因。 Bcl11a 对于 B 细胞发育至关重要，B 细胞发育的 Bcl11a 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。相反，Rit1/Bcl11b 已被确定为小鼠胸腺淋巴瘤的肿瘤抑制因子。小鼠发现，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显着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。杂合子小鼠在没有照射的情况下，在 300 天龄时经常出现胸腺淋巴瘤。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，Bcl11 蛋白的减少诱导细胞凋亡。这些结果表明 Bcl11b 可能相互作用。与 Chk1 一起作用并发挥基因组稳定功能。对转基因小鼠的分析表明， NUP98-HOXA9 诱导骨髓祖细胞的 G-CSF 过敏，通过逆转录病毒插入突变，发现新的 5 个基因是 NUP98-HOXA9 在白血病发生中的协同基因，其中 Fcgr2b 被发现与人类血液恶性肿瘤有关。对于理解人类白血病发生的分子机制很重要此外，MAPK 信号分子和 Mel1 被确定为候选分子。 NUP98-HOXA9 和 HOX 辅因子的协同基因较少。

项目成果

Involvement of V(D)J recombinase in generation of intragenic deletions of Rit1/Bcl11b tumor suppressor gene in γ-ray-induced thymic lymphomas and in normal thymus of the mouse.

V(D)J 重组酶参与 γ 射线诱导的小鼠胸腺淋巴瘤和正常胸腺中 Rit1/Bcl11b 肿瘤抑制基因的基因内缺失的产生。

• 发表时间: 2004
• 期刊: Carcinogenesis 25(6)
• 作者: Dongxing Wang;Kyoko S.Katsumata;Gyosuke Meshitsuka;J.Sakata
• 通讯作者: J.Sakata

Tsuruyama T: "Constitutive activation of Stat5a by retrovirus integration in early pre-B lymphomas of SL/Kh strain mice"Proc Natl Acad Sci USA. 99・12. 8253-8258 (2002)

Tsuruyama T：“SL/Kh 品系小鼠早期前 B 淋巴瘤中逆转录病毒整合对 Stat5a 的组成性激活”Proc Natl Acad Sci USA 99・12 (2002)。

Single translocation and double chimeric transcripts : DetectionofNUP98-HOXA9inmyeloidleukemiaswithHOXAllor HOXA13breaksofthechromosomaltranslocationt(7;11)(p15>p15).

单易位和双嵌合转录本：用 HOXAll 或 HOXA13 破坏染色体易位 t(7;11)(p15>p15) 检测髓样白血病中的 NUP98-HOXA9。

• 发表时间: 2002
• 期刊: Blood 99
• 作者: Fujino T;Suzuki A;Ito Y;Ohyashiki K;Hatano Y;Miura I;Nakamura T.
• 通讯作者: Nakamura T.

Liu, P et al.: "Bcl11a signaling is essential for B- and T-cell development."Nature Immunology. 4・6. 525-532 (2003)

Liu, P 等人：“Bcl11a 信号传导对于 B 细胞和 T 细胞的发育至关重要。”《自然免疫学》4·6 (2003)。

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.