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研究。每个模型中受试者的主要基因是EVI9/BCL11A和RIT1/BCL11B，它们均属于Bcl11基因家族，并分别在B细胞和T细胞的发展中起重要作用。 EVI9/BCL11A是人类B细胞癌基因和鼠髓样癌基因。我们已经透露，BCL11A对于使用BCL11A敲除模型的B细胞开发至关重要，而用于B细胞发育的BCL11A活性可能与其在E2A的免疫球蛋白重链增强子上的转录调节活性有关。还表明，BCL11A在T细胞发育中起着重要作用。相反，RIT1/BCL11b已被确定为小鼠胸腺淋巴瘤中的肿瘤抑制剂。 BCL11b敲除小鼠的分析表明，BCL11b对于T细胞的发展和BCL11b的丧失至关重要，导致T细胞的凋亡。 BCL11b - /+小鼠中的YMIC淋巴瘤的入射力明显高于通过□ - 辐射的野生型同窝仔。大约50％的淋巴瘤表明BCL11b的野生型等位基因损失。此外，Bcl11b - /+和p53 - /+双重杂合小鼠经常在未经辐射的情况下在300天内发育于300天的胸腺淋巴瘤。通过下调抗凋亡蛋白BCLXL，在S期的细胞周期停滞和CHK1磷酸化的抑制来减少BCL11蛋白诱导的凋亡。这些结果表明，Bcl11b可能与CHK1相互作用并在基因组稳定功能中起作用。分析转基因小鼠，结果表明NUP98-HOXA9诱导髓样祖细胞的G-CSF超敏反应。通过使用逆转录病毒插入诱变，将MEIS1和新的5个基因鉴定为白血病中NUP98-HOXA9的合作基因。在这些基因中，发现FCGR2B参与了人类血液学恶性肿瘤，表明该模型对于理解人白血病的分子机制很重要。此外，将MAPK信号分子和MEL1鉴定为NUP98-HOXA9和HOX副因素的候选合作基因。较少的

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

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)。

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.

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)。

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.