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

Anja Fischer, Thomas K. Albert, Natalia Moreno, Marta Interlandi, Jana Mormann, Selina Glaser, Paurnima Patil, Flavia W. 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 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 Leval, Reiner Siebert and Kornelius Kerl ()
Additional contact information
Anja Fischer: Ulm University Medical Center
Thomas K. Albert: University Children’s Hospital Münster
Natalia Moreno: University Children’s Hospital Münster
Marta Interlandi: University Children’s Hospital Münster
Jana Mormann: University Children’s Hospital Münster
Selina Glaser: Ulm University Medical Center
Paurnima Patil: Ulm University Medical Center
Flavia W. Faria: University Children’s Hospital Münster
Mathis Richter: University of Münster
Archana Verma: University Children’s Hospital Münster
Sebastian T. Balbach: University Children’s Hospital Münster
Rabea Wagener: Ulm University Medical Center
Susanne Bens: Ulm University Medical Center
Sonja Dahlum: Ulm University Medical Center
Carolin Göbel: Eppendorf (UKE)
Daniel Münter: University Children’s Hospital Münster
Clara Inserte: University of Münster
Monika Graf: University Children’s Hospital Münster
Eva Kremer: University Children’s Hospital Münster
Viktoria Melcher: University Children’s Hospital Münster
Gioia Stefano: Careggi University Hospital
Raffaella Santi: Careggi University Hospital
Alexander Chan: Memorial Sloan Kettering Cancer Center
Ahmet Dogan: Memorial Sloan Kettering Cancer Center
Jonathan Bush: British Columbia Children’s Hospital and Women’s Hospital and Health Center
Martin Hasselblatt: University Hospital Münster
Sylvia Cheng: University of British Columbia
Signe Spetalen: Oslo University Hospital
Alexander Fosså: Oslo University Hospital-Norwegian Radium Hospital
Wolfgang Hartmann: Gebäude D17
Heidi Herbrüggen: University Children’s Hospital Münster
Stella Robert: University Hospital Münster
Florian Oyen: Eppendorf (UKE)
Martin Dugas: University of Münster
Carolin Walter: University of Münster
Sarah Sandmann: University of Münster
Julian Varghese: University of Münster
Claudia Rossig: University Children’s Hospital Münster
Ulrich Schüller: Eppendorf (UKE)
Alexandar Tzankov: University Hospital Basel
Martin B. Pedersen: Aarhus University Hospital
Francesco A. d’Amore: Aarhus University Hospital
Karin Mellgren: The Queen Silvia Children’s Hospital
Udo Kontny: RWTH Aachen University Hospital
Venkatesh Kancherla: Lausanne University Hospital
Luis Veloza: Lausanne University Hospital
Edoardo Missiaglia: Lausanne University Hospital
Virginie Fataccioli: Université Paris-Est
Philippe Gaulard: Université Paris Est Créteil
Birgit Burkhardt: University Children’s Hospital Münster
Oliver Soehnlein: University of Münster
Wolfram Klapper: University Hospital Schleswig-Holstein
Laurence Leval: Lausanne University Hospital
Reiner Siebert: Ulm University Medical Center
Kornelius Kerl: University Children’s Hospital Münster

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52826-0

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