Abstract
Adult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells that are infected with human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL can be detected early in HTLV-1-carriers through quantification of T-cell receptor (TCR)Vβ subunit diversity on T-cells infected with HTLV-1 (CD3+ CCR4+ CD26− T-cells) using an ‘oligoclonality index’ (OCI-flow). We established a reference range for OCI-flow by analysing peripheral blood mononuclear cells (PBMCs) from HTLV-1-carriers who had not developed ATL in a median of 10.5 years follow up (n = 38) and patients with ATL (n = 30). In the third cohort of HTLV-1-carriers with no history or clinical evidence of ATL (n = 106), 19% of high proviral load (PVL, ≥4 copies of HTLV-1/100 PBMCs) carriers had an OCI-flow in the ATL range, >0.770. Carriers with an OCI-flow >0.770 (n = 14) had higher lymphocyte counts and PVLs and were more likely to have a family history of ATL than carriers with OCI-flow ≤0.770. ATL subsequently developed in two of these 14 carriers but no carriers with OCI-flow ≤0.770 (p = 0.03, cumulative follow-up 129 person-years). This method can be used to identify a subset of high-PVL HTLV-1-carriers at increased risk of developing ATL who may benefit from intervention therapy, prior to the detection of disease.
Highlights
There is an urgent clinical need for new approaches to improve the dismal prognosis of adult T cell leukaemia/lymphoma (ATL)
Oligoclonality of human T cell leukaemia virus type 1 (HTLV-1)-infected cells Oligoclonality of HTLV-1-infected cells was assessed by quantifying TCRVβ subunit expression by CD4+ CD3+ chemokine receptor type 4 (CCR4)+ CD26− and CD8+ CD3+ CCR4+ CD26− peripheral blood mononuclear cells (PBMCs) in the training cohorts: (Table 1): the No-ATL cohort (n = 38 HTLV-1 carriers who did not transform during a median follow-up of 127 months, range: 84–225 months), and the ATL cohort (n = 30, all subtypes of ATL, Supplementary Table 1)
In subjects with oligoclonality index (OCI)-flow ≤ 0.770 (n = 92), there was no significant difference in Ki-67 expression between CCR4+ CD26− Vβ2+ cells and other CCR4+ CD26− cells (p = 0.36, Fig. 3F). For both clinicians and HTLV-1 carriers, the probability of developing ATL is of frequent concern
Summary
There is an urgent clinical need for new approaches to improve the dismal prognosis of adult T cell leukaemia/lymphoma (ATL). The development of novel, welltolerated therapeutics which can target both premalignant and malignant cells has raised the possibility of preventing ATL by treating those who are most at risk of transformation in the premalignant stage. These individuals can be identified through serological testing for human T cell leukaemia virus type 1 (HTLV-1), who have a 5% lifetime risk of developing ATL1. ATL occurs almost exclusively in carriers who have a high PVL, and have a ~20% lifetime risk of ATL2. Between 104 and 105 distinct infected T cell clones circulate in asymptomatic HTLV-1 carriers[7]
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