Cytogentic analysis of the mechanism of adult T cell leukemia development

成人T细胞白血病（ATL）是一种致命的T细胞恶性肿瘤，在感染人类T细胞白血病病毒I型（HTLV-l）后长期发生。我们之前报道了NF-κB在ATL细胞中被组成性激活，尽管几乎检测不到病毒蛋白的表达，包括已知持续激活NF-κB的Tax。在这里，我们证明了不表达可检测的Tax蛋白的ATL细胞表现出组成型1KB激酶（IKK）活性。转染研究显示，在ATL细胞中，IKK1的显性阴性形式，而IKK2或NF-κB必需调节剂（NEMO）的显性阴性形式，抑制了NF-κB的活性。这种IKK活性伴随着p52的表达升高，表明最近描述的N - F-KB激活的非典型途径在ATL细胞中起作用。我们最终发现，在htlv -l感染的T细胞中，一种超抑制形式的IKBcL对NE-KB的特异性抑制会导致细胞死亡，无论Tax表达如何，这为NF-KB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细胞中通过不同于税收介导的IKK激活的细胞机制被组成性激活。进一步阐明这种细胞机制将有助于建立治疗ATL的基本原理。

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.