CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma

Commun Biol. 2022 Nov 29;5(1):1309. doi: 10.1038/s42003-022-04284-x.

Abstract

Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4+ T cell-specific CARD11(E626K) and/or CD4+ T cell-specific HBZ, namely CARD11(E626K)CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes' pathogenetic effects. CARD11(E626K)CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4+ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Basic-Leucine Zipper Transcription Factors* / genetics
  • CARD Signaling Adaptor Proteins
  • Guanylate Cyclase
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell* / genetics
  • Lymphoma*
  • Mice
  • Mice, Transgenic
  • Mutation
  • NF-kappa B / genetics
  • Retroviridae Proteins

Substances

  • Basic-Leucine Zipper Transcription Factors
  • CARD Signaling Adaptor Proteins
  • CARD11 protein, human
  • Card11 protein, mouse
  • Guanylate Cyclase
  • HBZ protein, human T-cell leukemia virus type I
  • NF-kappa B
  • Retroviridae Proteins