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Cytogentic analysis of the mechanism of adult T cell leukemia development

成人T细胞白血病发生机制的细胞遗传学分析

基本信息

批准号：
14570965
负责人：
YAMAOKA Shoji
金额：
$ 2.24万
依托单位：
Tokyo Medical Mand Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570965/
关键词：
ATL leukemogenesis NF-κB IKK NFKB2 NF-kappa B HTLV-1 IKK1 NEMO

项目摘要

Adult T-cell leukemia (ATL) is a fatal T cell malignancy that arises long after infection with human T-cell leukemia virus type I (HTLV-l). We reported previously that NF-κB was constitutively activated in ATL cells, although expression of the viral proteins was barely detectable including Tax which was known to persistently activate NF-κB. Here we demonstrate that ATL cells that do not express detectable Tax protein exhibit constitutive 1KB kinase (IKK) activity. Transfection studies revealed that a dominant negative form of IKK1, and not of IKK2 or NF-κB essential modulator (NEMO) suppressed constitutive NF-κB activity in ATL cells. This IKK activity was accompanied by elevated expression of p52, suggesting that the recently described non-canonical pathway of N F-KB activation operates in ATL cells. We finally show that specific inhibition of NE-KB by a super-repressor form of IKBcL in HTLV-l-infected T cells results in cell death regardless of Tax expression, providing definitive evidence of an essential role for NF-KB in the survival of ATL cells. In conclusion, the IKK complex is constitutively activated in ATL cells through a cellular mechanism distinct from that of Tax-mediated IKK activation. Further elucidation of this cellular mechanism should contribute to establishing a rationale for treatment of ATL.

成人T细胞白血病（ATL）是一种致命的T细胞恶性肿瘤，在感染人T细胞白血病病毒I型（HTLV-1）后很久才出现。我们以前报道过NF-κB在ATL细胞中被组成性激活，尽管病毒蛋白的表达几乎检测不到，包括已知持续激活NF-κB的Tax。在这里，我们证明，ATL细胞，不表达可检测的Tax蛋白表现出组成型1 KB激酶（IKK）的活动。转染研究表明，IKK 1的显性负性形式，而不是IKK 2或NF-κB必需调节因子（NEMO）抑制ATL细胞中的组成型NF-κB活性。这种IKK活性伴随着p52表达的升高，表明最近描述的NF-κ B活化的非经典途径在ATL细胞中起作用。我们最终表明，在HTLV-1感染的T细胞中，通过IKBcL的超阻遏物形式对NE-KB的特异性抑制导致细胞死亡，而不管Tax表达如何，这为NF-κ B在ATL细胞存活中的重要作用提供了明确的证据。总之，IKK复合物在ATL细胞中通过不同于Tax介导的IKK激活的细胞机制被组成性激活。进一步阐明这一细胞机制将有助于确立治疗ATL的基本原理。