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

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-NOS...

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Main Authors: Fischer, Anja (Author) , Albert, Thomas K. (Author) , Moreno, Natalia (Author) , Interlandi, Marta (Author) , Mormann, Jana (Author) , Glaser, Selina (Author) , Patil, Paurnima (Author) , de Faria, Flavia W. (Author) , Richter, Mathis (Author) , Verma, Archana (Author) , Balbach, Sebastian T. (Author) , Wagener, Rabea (Author) , Bens, Susanne (Author) , Dahlum, Sonja (Author) , Göbel, Carolin (Author) , Münter, Daniel (Author) , Inserte, Clara (Author) , Graf, Monika (Author) , Kremer, Eva (Author) , Melcher, Viktoria (Author) , Di Stefano, Gioia (Author) , Santi, Raffaella (Author) , Chan, Alexander (Author) , Dogan, Ahmet (Author) , Bush, Jonathan (Author) , Hasselblatt, Martin (Author) , Cheng, Sylvia (Author) , Spetalen, Signe (Author) , Fosså, Alexander (Author) , Hartmann, Wolfgang (Author) , Herbrüggen, Heidi (Author) , Robert, Stella (Author) , Oyen, Florian (Author) , Dugas, Martin (Author) , Walter, Carolin (Author) , Sandmann, Sarah (Author) , Varghese, Julian (Author) , Rossig, Claudia (Author) , Schüller, Ulrich (Author) , Tzankov, Alexandar (Author) , Pedersen, Martin B. (Author) , d’Amore, Francesco A. (Author) , Mellgren, Karin (Author) , Kontny, Udo (Author) , Kancherla, Venkatesh (Author) , Veloza, Luis (Author) , Missiaglia, Edoardo (Author) , Fataccioli, Virginie (Author) , Gaulard, Philippe (Author) , Burkhardt, Birgit (Author) , Soehnlein, Oliver (Author) , Klapper, Wolfram (Author) , de Leval, Laurence (Author) , Siebert, Reiner (Author) , Kerl, Kornelius (Author)
Format: Article (Journal)
Language:English
Published: 03 October 2024
In: Nature Communications
Year: 2024, Volume: 15, Pages: 1-18
ISSN:2041-1723
DOI:10.1038/s41467-024-52826-0
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-024-52826-0
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-024-52826-0
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Author Notes: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

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520 |a 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. 
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