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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年10月3日

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  • Anja Fischer,
  • Thomas K. Albert,
  • Natalia Moreno,
  • Marta Interlandi,
  • Jana Mormann,
  • Selina Glaser,
  • Paurnima Patil,
  • Flavia W. de Faria,
  • Mathis Richter,
  • Archana Verma,
  • Sebastian T. Balbach,
  • Rabea Wagener,
  • Susanne Bens,
  • Sonja Dahlum,
  • Carolin Göbel,
  • Daniel Münter,
  • Clara Inserte,
  • Monika Graf,
  • Eva Kremer,
  • Viktoria Melcher,
  • Gioia Di Stefano,
  • Raffaella Santi,
  • Alexander Chan,
  • Ahmet Dogan,
  • Jonathan Bush,
  • Martin Hasselblatt,
  • Sylvia Cheng,
  • Signe Spetalen,
  • Alexander Fosså,
  • Wolfgang Hartmann,
  • Heidi Herbrüggen,
  • Stella Robert,
  • Florian Oyen,
  • Martin Dugas,
  • Carolin Walter,
  • Sarah Sandmann,
  • Julian Varghese,
  • Claudia Rossig,
  • Ulrich Schüller,
  • Alexandar Tzankov,
  • Martin B. Pedersen,
  • Francesco A. d’Amore,
  • Karin Mellgren,
  • Udo Kontny,
  • Venkatesh Kancherla,
  • Luis Veloza,
  • Edoardo Missiaglia,
  • Virginie Fataccioli,
  • Philippe Gaulard,
  • Birgit Burkhardt,
  • Oliver Soehnlein,
  • Wolfram Klapper,
  • Laurence de Leval,
  • Reiner Siebert,
  • Kornelius Kerl

摘要

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.