It has been postulated by some, and strongly adopted by others, that HTLV-1 infection results in a state of genomic instability that sets the stage for accumulation of the events necessary for leukemogenesis (reviewed in refs. 4
). The predicted randomness of such genomic insults is an attractive element of this hypothesis in that it helps explain the long latent period following virus infection prior to disease development. However, if the molecular events are random, then why is there a specific cell type and disease type? In this respect, cell-specific restriction of molecular activities would be a reasonable explanation. The reported oncogenic capabilities of the viral protein Tax revolve around the ability of Tax to alter cell cycle, genomic instability, and apoptosis in a not necessarily unrelated fashion (4
). All of these Tax-related activities were confirmed in the ex vivo model presented by Sibon et al. except for apoptosis (3
). All in all, the most intriguing consistency may be the result that Tax-expressing cells displayed genetic instability and that de novo expression of Tax resulted in the accumulation of cells in a higher ploidy state (>2N). Certainly it is clear that induction of genomic instability, which Sibon et al. show is restricted to CD4+
cells, is a compelling precondition for cellular transformation in a variety of cancer models. This dichotomy between CD4+
cells for accumulation of genomic aberrations, indicative of loss of genomic integrity, is alone sufficient to explain the restriction of ATLL to the CD4+
cell type and suggests that Tax activities differ between T cell subtypes.
As with all molecularly defined systems that utilize cell lines and transient overexpression approaches, arguments abound with respect to which cell system is appropriate and which results are relevant to human disease. In point of fact, although there is universal agreement on the induction of genomic instability, there are contradictory reports with respect to the ability of Tax to induce apoptosis (6
). Likewise, although most studies support the hypothesis that Tax alters the cell cycle (10
), some studies fail to make this observation (13
). Clearly the results derived from the ex vivo system employed by Sibon et al. (3
) demonstrate that Tax expression correlated with the increased percentage of CD4+
cells residing in S and G2
M phases but had no such effect in CD8+
cells. Thus, although each of the molecular systems employed in the transient overexpression studies can shed light on Tax activities, the systems that reproduce genomic instability and altered cell cycle distribution are more biologically relevant to ATLL development.