Telomerase regulation in HTLV-I infection.

In this issue of Blood, Bellon and Nicot describe an elegant mechanism used by HTLV-I to up-regulate telomerase gene expression and function in the absence of the viral tax oncoprotein. A dult T-cell leukemia was first reported as an entity in Blood in 1977. 1 Three years later, Gallo et al identified the human T-cell leukemia/lymphoma virus-I (HTLV-I), a deltaretrovirus, as the causative agent for this debilitating disease. 2 Currently, the estimated number of people infected with HTLV-I worldwide is between 15 and 25 million. However , due to insidious characteristics of this virus, most HTLV-1–infected individuals remain asymptomatic for at least 20 to 30 years before developing HTLV-related clinical disorders. Besides causing adult T-cell leukemia and lymphoma (ATLL), HTLV-I has been associated with other human diseases, including a neurologic disorder known as HLTV-I– associated myelopathy/tropical spastic para-paresis, and perhaps other hematologic and nonhematologic disorders. HTLV-I has been intensely studied, primarily because it has the capacity to transform primary human T cells in vitro and in vivo. 3 To convert a normal T cell to a leukemic cell, the HTLV-I tax oncoprotein must participate in several cellular pathways in order to overcome innate cellular barriers to transformation. 4 To achieve clonal expansion in the early phase of viral infection, HTLV-I–infected cells also acquire an increased capacity to rep-licate DNA. The complete replication of linear chromosomal DNA relies on the enzymatic activity of a specialized cellular RNA-dependent DNA polymerase (telomerase) that synthesizes telomeric sequences at the 3Ј ends of linear chromosomes. 5 The tax protein of HTLV-I has been shown to up-regulate expression of the catalytic protein subunit of telomerase (hTERT) in infected cells, via the nuclear factor ␬B (NF-␬B) signaling pathway. 6 Clonal expansion of HTLV-I–infected cells is also dependent on the presence of in-terleukin-2 (IL-2), as this cytokine is required for the differentiation and long-term proliferation of T cells. 7 However, as noted by Bellon and Nicot, expression of tax protein in IL-2– dependent cells and in primary tissues of ATLL patients is almost undetectable, yet these cells retain high levels of telomerase en-zymatic activity. These observations suggest an alternative mechanism for telomerase activation , independent of the viral tax protein. To establish a link between IL-2 and telomer-ase activation, the authors withdraw this growth factor in cultures of immortalized HTLV-I–infected cells and show that telom-erase activity is reduced. By using known pharmacological inhibitors of PI3K, a downstream target …