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-NOS<sup>SMARCB1-</sup>, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS<sup>SMARCB1-</sup> 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-NOS<sup>Smarcb1-</sup>. 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-NOS<sup>SMARCB1-</sup> within the TME.

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Publication Details

Journal
Nature Communications
Published
2024-10-03
DOI
https://doi.org/10.1038/s41467-024-52826-0
Citations
2
Primary Topic
Chromatin Remodeling and Cancer
Type
article
Field-Weighted Citation Impact
0.47

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article

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

Martin Dugas, Mathis Richter, Wolfgang Hartmann, Susanne Bens et al.
2 citations
Nature Communications
Chromatin Remodeling and Cancer
0.47
article

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

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

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-NOS<sup>SMARCB1-</sup>, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS<sup>SMARCB1-</sup> 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-NOS<sup>Smarcb1-</sup>. 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-NOS<sup>SMARCB1-</sup> within the TME.

Nature CommunicationsVol. 15(1)
Oslo University Hospital (NO), Memorial Sloan Kettering Cancer Center (US), University of British Columbia (CA), Inserm (FR), Universität Hamburg (DE), University of Oslo (NO), Universität Ulm (DE), Université Paris-Est Créteil (FR), Aarhus University (DK), Heidelberg University (DE), University of Münster (DE), Norwegian Cancer Society (NO), Sahlgrenska University Hospital (SE), University Hospital Heidelberg (DE), Aarhus University Hospital (DK), University Hospital of Basel (CH), Assistance Publique – Hôpitaux de Paris (FR), University Hospital Münster (DE), University Medical Center Hamburg-Eppendorf (DE), Kinderkrebs-Zentrum Hamburg (DE), University Hospital Schleswig-Holstein (DE), Azienda Ospedaliero-Universitaria Careggi (IT), Universitätsklinikum Aachen (DE), Hôpitaux Universitaires Henri-Mondor (FR), BC Children's Hospital (CA), B.C. Women's Hospital & Health Centre (CA), RWTH Aachen University (DE), University of Lübeck (DE), University of Lausanne (CH)
Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsche Krebshilfe, Deutsche Kinderkrebsstiftung
Openalex Percentile: Top 35%
Chromatin Remodeling and Cancer
0.47
DOIOpen Access PDFOpenAlex
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