Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas

Nat Commun. 2024 Oct 3;15(1):8571. doi: 10.1038/s41467-024-52826-0.

Abstract

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOSSMARCB1-, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOSSmarcb1-. In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOSSMARCB1- within the TME.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA Methylation*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Histone Deacetylase Inhibitors* / pharmacology
  • Humans
  • Lymphoma, T-Cell, Peripheral* / drug therapy
  • Lymphoma, T-Cell, Peripheral* / genetics
  • Lymphoma, T-Cell, Peripheral* / metabolism
  • Lymphoma, T-Cell, Peripheral* / pathology
  • Male
  • Mice
  • SMARCB1 Protein* / genetics
  • SMARCB1 Protein* / metabolism
  • Single-Cell Analysis
  • Tumor Microenvironment* / drug effects
  • Tumor Microenvironment* / genetics
  • Vorinostat / pharmacology

Substances

  • SMARCB1 Protein
  • Histone Deacetylase Inhibitors
  • SMARCB1 protein, human
  • Smarcb1 protein, mouse
  • Vorinostat