Figure 6. Model of leukemogenesis by HTLV-1/BLV.

After infection by HTLV-1/BLV the fate of a given infected T-cell/B-cell clone depends on the proviral integration site within the host genome, the expression of TAX and HTLV-1-HBZ/BLV-AS, the host CTL response to HTLV-1/BLV antigens and somatic mutations in the host genome. Asymptomatic polyclonal stage: the integration of HTLV-1/BLV proviruses in the vicinity of cancer drivers causes their perturbation and hence favours the persistence/survival/expansion of the corresponding infected clone (green clones). Clones in which proviral insertions do not affect cancer drivers show a modest survival (purple clones). The relative contribution of each infected clone to the polyclonal population of infected cells results from the balance between cancer driver perturbation, expression of TAX and HBZ/AS that both promote cell growth, and negative selection by the host CTL response. The prolonged life-span of clones in which cancer drivers are perturbed favours the acquisition of further somatic alterations in the host genome. Malignant stage: the accumulation of somatic changes ultimately precipitates the progression of one of the clones to full-blown malignancy (green clone—red integration and orange leukaemic clone). The tumour clone originates from an expanded/persistent clone yet not necessarily the most abundant one. The absence of TAX expression in the tumour clone confers a survival advantage through escape from the strong CTL immune response.