Clonality in adult T-cell leukaemia/lymphoma

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong within the infected host by driving expansion of infected CD4+T-cells. It is the cause of adult T-cell leukaemia/lymphoma (ATL), an aggressive CD4+ T-cell malignancy, which arises in approximately 5% of individuals typically following decades of asymptomatic infection. The reasons why some individuals develop ATL remain unknown. In this laboratory a novel customised high throughput sequencing and bioinformatic method has been developed in order to map and accurately quantify the proviral integration sites within each host genome in order to identify clonal populations within each host. In this study I aimed first to test the hypothesis that there is a single provirus integrated into each host genome, and secondly to test the hypothesis that the site of retroviral integration determines the risk of leukaemia. In order to quantify the average number of proviral integration sites in each host cell, we isolated infected T-cells from the peripheral blood of infected individuals by limiting dilution cloning. Integration site analysis of these clones revealed that in natural infection each T-cell clone carries a single integrated provirus. This work formed the basis of a publication in the journal Blood (Cook et al 2012). I describe the systematic analysis of the clonality, structure and the integrity of the proviral tax gene in a large cohort of ATL patients (n=197). I correlate these findings with the clinical subtype of ATL and the landscape of the host genome flanking the proviral integration site. Based upon our findings we conclude that the integration site in cis does not directly cause leukaemogenesis and hypothesise that the absolute number of infected clones within an individual, and not oligoclonal proliferation, predisposes to malignant transformation.