Whole-genome landscape of adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3′-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors suggesting their activities in ATL. By combining the analyses for coding and non-coding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into two molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms

“…“Chronic lymphoproliferative disorder of NK cells” in WHO-HAEM4R has been renamed NK-large granular lymphocytic leukaemia (NK-LGLL) , given recent evidence that this is a monoclonal or oligoclonal expansion of NK cells that has many similarities with T-LGLL. Genetic analyses of adult T-cell leukaemia/lymphoma (ATLL) have revealed novel events that highlight the importance of immune evasion including CTLA4 :: CD28 and ICOS :: CD28 fusions, REL C-terminal truncations [ 215 , 216 ], recurrent alterations in HLA-A and HLA-B and structural variations disrupting the 3′-untranslated region of CD274 ( PD-L1) [ 217 ]. Furthermore, the frequency and pattern of somatic alterations appear to be correlated with clinical behavior.…”

Specialized Intercellular Communications via Tunnelling Nanotubes in Acute and Chronic Leukemia

“…Adult T cell leukemia/lymphoma (ATL) is a malignancy of peripheral T lymphocytes provoked by human T cell leukemia virus type 1 infection (HTLV-1). This leukemia is extremely resistant to treatment, and it is estimated that at least 5-10 million patients are infected with HTLV-1, the first human oncogenic retrovirus detected [142].…”

CD58 as a biomarker for prognosis and immune infiltration in hepatocellular carcinoma

“…Previous studies found that CD58 is a glycoprotein expressed on the surface of B cells, T cells, monocytes, granulocytes and thymic epithelial cells, an important member of the immune superprotein family, and has a role in promoting cell adhesion [19]. We found that the main studies of CD58 focused mainly on hematological tumors [23][24][25]27], skin diseases [35], where CD58 plays a rather important role through different mechanisms. There are also a few other malignant tumors, such as cervical cancer[28],…”

“…Aggressive ATLL is refractory to conventional chemotherapy and has a poor prognosis. The genetic pro le of ATLL shows frequent alterations in genes associated with immune surveillance, including major histocompatibility complex (MHC) class I, CD58 antigen, programmed cell death ligand 1 (PDL1), HLA-A/B, FAS [23,24]. Downregulation of CD58 allows immune escape occur [25].…”