Adult T-cell leukemia-lymphoma as a viral disease: Subtypes based on viral aspects

Abstract

Adult T-cell leukemia-lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Among HTLV-1 encoded genes, HTLV-1 bZIP factor (HBZ) and tax are critical for the leukemogenesis of ATL. Adult T-cell leukemia-lymphoma needs a long latent period before onset, indicating that both viral genes and alterations (genetic and epigenetic) of the host genome play important roles for leukemogenesis. Viral genes influence genetic and epigenetic changes of the host genome, indicating that the virus is of primary importance in leukemogenesis. HBZ is expressed in all ATL cases, whereas Tax expression is heterogeneous among ATL cases. Different patterns of viral gene expression in tumors are also observed for Epstein-Barr virus. We propose three subtypes of ATL cases based on Tax expression: high, intermittent, and lost expression. HBZ is detected in all ATL cases. Approximately 25% of all ATL cases lost Tax expression at infection of HTLV-1, indicating that HBZ is the only viral gene responsible for leukemogenesis in addition to genetic and epigenetic changes of the host genes in these ATL cases. The host immune responses to Tax are also implicated in the heterogeneity of ATL. Thus, ATL is a heterogeneous disease in terms of its viral gene expression, which is important for pathogenesis of this intractable lymphomatous neoplasm.

Keywords: ATL; CCR4; CTL; EBV; HBZ; HTLV-1; Tax.

FIGURE 1

Characteristics of Tax and human T‐cell leukemia virus type 1 (HTLV‐1) bZIP factor (HBZ) in HTLV‐1 infection and adult T‐cell leukemia‐lymphoma (ATL). Tax is essential for de novo infection and intermittent expression of almost all viral proteins, and has high immunogenicity. HBZ is essential for proliferation, and shows constant expression and low immunogenicity

FIGURE 2

Human T‐cell leukemia virus type 1 (HTLV‐1) provirus and the expression pattern of Tax. A, Complete HTLV‐1 provirus. Adult T‐cell leukemia‐lymphoma (ATL) cells with intact provirus can intermittently express Tax along with constant expression of HTLV‐1 bZIP factor (HBZ). B, Provirus with inactivated Tax expression. Tax expression is absent due to: (a) nonsense mutation of the tax gene; (b) deletion of the 5′‐long terminal repeat (LTR); or (c) DNA methylation of the 5′‐LTR. ATL cells with these proviruses cannot express Tax, whereas they constantly express HBZ. The frequencies of the different kinds of proviruses among ATL cases are shown on the right

FIGURE 3

Different human T‐cell leukemia virus type 1 (HTLV‐1) proviruses and expression patterns of tax and HTLV‐1 bZIP factor (HBZ) in carriers and adult T‐cell leukemia‐lymphoma (ATL). In carriers, multiple different proviruses exist. In ATL, Tax expression is disrupted in approximately half of cases by one of three mechanisms: (a) nonsense mutation of the tax gene; (b) deletion of the 5′‐long terminal repeat (LTR); or (c) DNA methylation of the 5′‐LTR. In most other cases, Tax is transiently expressed as it is in MT‐1 cells