Integrated molecular analysis of adult T cell leukemia/lymphoma

Abstract

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

Galectin-9 as a Predictive Marker for the Onset of Immune-Related Adverse Effects Associated with Anti-CCR4 MoAb Therapy in Patients with Adult T Cell Leukemia

“…We previously proposed that stimulation of the TCR/CD3 complex, represented by a low density of the CD3 antigen, is a unique feature of ATL/ATLL cells . A recent integrated molecular study of the ATL/ATLL genome also showed frequent alteration of TCR-nuclear factor κB signaling, which may suggest stimulation of ATL/ATLL cells through the TCR (Kataoka et al 2015). Gal-9 shows apoptotic activity toward tumor cells or T cells (Fujihara et al 2013), and it should be studied whether Gal-9 has an apoptotic effect on fresh ATL/ATLL cells.…”

Reducing the global burden of HTLV-1 infection: An agenda for research and action

“…-further develop whole-genome sequencing to identify hostassociated driver mutations in all conditions, as recently performed for ATL (Kataoka et al, 2015); -correlate the emergence of driver mutations with disease onset; -develop assays allowing early prediction of differential disease development and the identification of progression.…”

“…-genes promoting viral replication and persistence (Tax and HBZ) (Matsuoka and Jeang, 2007); -modes of viral entry and replication (infectious and mitotic cycles) (Ghez et al, 2010;Boxus et al, 2012;Gillet et al, 2011Gillet et al, , 2013Sibon et al, 2006); -genomic and epigenetic mechanisms leading to ATL (oncogenic stress, driver mutations) (Kataoka et al, 2015;Yamagishi et al, 2012); -the role of the immune response in the control of infection (Asquith and Bangham, 2008); -the pathogenic potential of HTLV-2, -3 and -4 (Calattini et al, 2006).…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…High-throughput methodologies were used to identify the cell of origin and to characterize commonly altered pathways in PTCL [51,59–67]. These efforts were successful in defining characteristic gene expression profiles for AITL, ALK + ALCL, ATLL, and PTCL-NOS, identifying recurrent mutations and recognizing specific subtypes, which can now help to support correct diagnosis and classification of patients to distinct disease subgroups with different prognoses [46,59,60,62,63].…”