Cytogentic analysis of the mechanism of adult T cell leukemia development

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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.