Genetic alterations in adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis. It is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. A long latency period from HTLV-1 infection to ATL onset suggests that not only HTLV-1 proteins, such as Tax and HBZ, but also additional genetic and/or epigenetic events are required for ATL development. Although many studies have demonstrated the biological functions of viral genes, alterations of cellular genes associated with ATL have not been fully investigated. Recently, a large-scale integrated genetic analysis revealed the entire landscape of somatic aberrations in ATL. This neoplasm is characterized by frequent gain-of-function alterations in components of the T-cell receptor/NF-κB signaling pathway, including activating mutations in the PLCG1, PRKCB, CARD11 and VAV1 genes, and CTLA4-CD28 and ICOS-CD28 fusions. Importantly, molecules associated with immune surveillance, such as HLA-A/B, CD58 and FAS, are affected recurrently. Among them, one notable lesion occurs as frequent structural variations that truncate the PD-L1 3'-untranslated region, leading to its overexpression. Other genetic targets include transcription factors (IRF4, IKZF2, and GATA3) and chemokine receptors (CCR4, CCR7 and GPR183), which are functionally relevant in normal T cells. A substantial proportion of ATL cases show widespread accumulation of repressive epigenetic changes, such as trimethylation of histone H3 lysine 27 and DNA hypermethylation of CpG islands, which coordinately modulate multiple pathways, including Cys2-His2 zinc finger genes involved in silencing retroelements. Here we review the current understanding of the genetic/epigenetic aberrations in ATL, focusing on their relevance in its molecular pathogenesis.

Keywords: Adult T-cell leukemia/lymphoma; PD-L1; T-cell receptor/NF-κB signaling; human T-cell leukemia virus type-1; next-generation sequencing.

Figure 1

Predominance of gain‐of‐function mutations in the TCR/NF‐κB pathway. Frequent gain‐of‐function alterations in TCR/NF‐κB and other related pathways, as well as loss‐of‐function alterations of their negative regulators are observed in adult T‐cell leukemia/lymphoma (ATL). The major driver alterations are summarized with their frequencies. Amp, amplification; Del, deletion; Mut, mutation.

Figure 2

Multiple genetic lesions associated with immune evasion. A variety of molecules associated with immune evasion are altered in adult T‐cell leukemia/lymphoma (ATL). The commonly affected molecules and their ligands or receptors are shown with the frequencies of their alterations (upper). The genetic and epigenetic mechanisms underlying the alterations of PD‐L1 and major histocompatibility complex (MHC) class 1 genes are shown (lower). PD‐L1 overexpression is caused by structural variations (SV) inducing the 3′‐UTR truncation, such as deletions, inversions, duplications and translocations (lower left). MHC class 1 genes are inactivated by either nonsense and frameshift mutations (Mut), copy number deletions (Del) or hypermethylation of promoter CpG islands (lower right).

Figure 3

Multiple layers of epigenetic repression in adult T‐cell leukemia/lymphoma (ATL). Widespread accumulation of epigenetic repressive changes, such as H3K27 trimethylation (H3K27 me3) and DNA hypermethylation, are observed in ATL. H3K27 me3 accumulation is caused by polycomb repressive complex 2 activation and is usually associated with loss of H3K4 trimethylation (H3K4 me3). These epigenetic mechanisms are thought to coordinately cause NF‐κB pathway activation, MHC class 1 gene inactivation and C2H2 zinc finger gene suppression.

Figure 4

Human T‐cell leukemia virus type‐1 (HTLV‐1) proviral genome and transcription. HTLV‐1 proviral genome, sense and antisense transcripts, and abnormal fusion transcripts between viral and host sequences are shown. Sense strand genes, including tax, are frequently inactivated by deteriorating mutations and deletions and promoter hypermethylation. Viral transcripts predominantly originate in the antisense direction. Two different forms of fusion transcripts between host and viral sequences (read‐through and spliced transcripts) are frequently observed in adult T‐cell leukemia/lymphoma (ATL).