Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells

Abstract

Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor-NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7 Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1-infected CD4⁺ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

Figure 1.

Comparison of molecular abnormalities between HTLV-1–infected T cells and transformed ATL cells. Many aspects of the ATL cell phenotype share common characteristics with that of untransformed HTLV-1–infected T cells expressing viral proteins, including Tax. Tax was shown to induce the majority of molecular changes observed in HTLV-1–infected cells, most of which are preserved in ATL cells that do not express Tax. Thus, this phenomenon is sometimes referred to as the signature of Tax. CARD11, caspase recruitment domain-containing protein 11; GPR183, G-protein coupled receptor 183; NRXN3, neurexin-3; PLCG1, phospholipase C, γ 1; PRKCB, protein kinase C β.

Figure 2.

Schematic summary of genetic abnormalities in ATL cells. (A) Accumulation of mutations in TCR signaling and NF-κB pathway. (B) examples of minor mutations. Intragenic deletions and mutations in genes other than those involved in TCR signaling. (C) possible effects of cytosine guanine dinucleotide (CpG) island methylator phenotype (CIMP). CSNK2B, casein kinase II subunit β; CSNK2A1, casein kinase 2 α 1; CSNK1A1, casein kinase 1 α 1; HNRNPA2B1, heterogeneous nuclear ribonucleoproteins A2/B1; IKZF2, zinc finger protein Helios.

Figure 3.

Epigenetic landscape of ATL cells. High levels of EZH2 expression is observed in HTLV-1–infected cells as well as in ATL cells. Tax and NF-κB can induce EZH2 expression. ATL cells are characterized by PRC2 overexpression and H3K27 m3 accumulation, the level of which appears to progress with clonal progression.

Figure 4.

Accumulation of H3K27m3 as the basis of ATL cell phenotype. PRC2-mediated accumulation of H3K27 me3 suppresses important genes such as tumor suppressors, miRNAs, epigenetic modifiers, and transcription factors, culminating in abnormalities in regulation of downstream genes that determine the phenotype of ATL cells.

Figure 5.

Schematic description of clonal progression and phenotypic changes. HTLV-1–infected T cells and ATL cells in vivo are now available for molecular analyses. Accumulating data indicate that epigenetic abnormalities occur early during leukemogenesis, as untransformed HTLV-1–infected cells show evidence of epigenetic abnormalities that are observed in ATL cells as well. The extent of clonality during HTLV-infection and progression to ATL have been characterized in detail by recent studies that provide information on clonal progression based on integration sites.

Figure 6.

Schematic presentation of the clonal progression and hierarchical structure of HTLV-1–infected T cells. A clone that is defined by the integration site contains subclones with different genetic abnormalities. Among these subclones, there is a hierarchical structure where T_SCM cells behave as ATL-initiating stem cells. T_CM, CD45RO⁺ central memory T cells; T_EM, CD45RO⁺ effector memory T cells; T_N, CD45RA⁺ naive T cells.