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

Cancer Sci. 2021 May;112(5):1688-1694. doi: 10.1111/cas.14869. Epub 2021 Mar 30.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents / therapeutic use
  • B-Lymphocytes / virology
  • Basic-Leucine Zipper Transcription Factors / genetics*
  • Basic-Leucine Zipper Transcription Factors / immunology
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Proliferation
  • Cell Transformation, Viral
  • Epigenesis, Genetic
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Leukemic
  • Gene Expression Regulation, Viral
  • Gene Products, tax / genetics*
  • Gene Products, tax / immunology
  • Gene Products, tax / metabolism
  • Herpesvirus 4, Human / genetics*
  • Human T-lymphotropic virus 1 / genetics*
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / genetics
  • Leukemia-Lymphoma, Adult T-Cell / immunology
  • Leukemia-Lymphoma, Adult T-Cell / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / virology*
  • Mice
  • Mice, Transgenic
  • RNA, Viral / genetics
  • Retroviridae Proteins / genetics*
  • Retroviridae Proteins / immunology
  • Retroviridae Proteins / metabolism
  • T-Lymphocytes, Regulatory / virology
  • Virus Replication / genetics

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Basic-Leucine Zipper Transcription Factors
  • Epstein-Barr virus encoded RNA 1
  • Epstein-Barr virus encoded RNA 2
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Gene Products, tax
  • HBZ protein, human T-cell leukemia virus type I
  • RNA, Viral
  • Retroviridae Proteins
  • mogamulizumab