gms | German Medical Science

In the last years several cases of Adult T-cell leukemia/lymphoma (ATLL), an aggressive, fatal malignancy of mature CD4+ T lymphocytes, were diagnosed in Germany. The disease is caused by the retrovirus human T-lymphotropic virus type 1 (HTLV-1). About 20 million individuals are infected worldwide, about 6000 in Germany. The malignancy develops after a 40–60-year period of clinical latency in about 3–5% of HTLV-1-infected individuals. The clinical symptoms are heterogeneous, lymph node swelling, skin lesions and hepatosplenomegaly are common. Depending on the subtype, the median survival is between 2 years and 13 months. ATLL cells contain the HTLV-1 provirus integrated into the host cell chromosome and are monoclonal in each case. A persistent oligo/polyclonal expansion of HTLV-1-bearing cells precedes ATLL, supporting the notion that the tumor cells arise from a clonally expanding non-malignant cell. The virus’s capacity to stimulate permanent T-lymphocyte growth could account for the clonal expansion of the T-lymphocytes in non-leukemic carriers A viral oncoprotein, Tax, confers the transforming properties on the virus. It is capable of immortalizing T-cells and is leukemogenic in transgenic mice. It interferes with normal cell cycle control by dysregulating control checkpoints. In particular, Tax is capable of stimulating the G1 phase by binding to and activating cyclin-dependent kinase holoenzymes. Moreover, Tax can stimulate or repress the expression of cellular proteins involved in cell survival and proliferation. Tax-mediated modulation of cellular gene expression may explain the resistance of HTLV-1-positive and ATLL cells to various proapoptotic stimuli. Among the genes of potential relevance for the survival of HTLV-1-transformed cells, we identified hiap-1/ciap-2 (human inhibitor of apoptosis 1). HIAP-1 represses apoptosis by inhibiting caspases 3, 7 and 9. A strong upregulation of HIAP-1 expression by Tax is a consistent feature of HTLV-1-transformed cell lines. Suppression of HIAP-1 expression by RNAi results in strongly reduced cellular proliferation, apoptosis and increased caspase 3/7 activity in HTLV-1-transformed cells. Thus, in infected lymphocytes the viral oncoprotein is not only required for stimulating proliferation but also for prevention of apoptosis.