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. 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

doi:10.1038/s41467-024-52826-0

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. 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 MelcherGioia 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

Department of Clinical Medicine - Department of Haematology

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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.

Original language	English
Article number	8571
Journal	Nature Communications
Volume	15
Issue	1
Pages (from-to)	8571
Number of pages	1
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-024-52826-0
Publication status	Published - 3 Oct 2024

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Fischer, A., Albert, T. K., Moreno, N., Interlandi, M., Mormann, J., Glaser, S., Patil, P., de Faria, F. W., Richter, M., Verma, A., Balbach, S. T., Wagener, R., Bens, S., Dahlum, S., Göbel, C., Münter, D., Inserte, C., Graf, M., Kremer, E., ... Kerl, K. (2024). Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas. Nature Communications, 15(1), 8571. Article 8571. https://doi.org/10.1038/s41467-024-52826-0

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title = "Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2024. The Author(s).",

year = "2024",

month = oct,

day = "3",

doi = "10.1038/s41467-024-52826-0",

language = "English",

volume = "15",

pages = "8571",

journal = "Nature Communications",

issn = "2041-1723",

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Fischer, A, Albert, TK, Moreno, N, Interlandi, M, Mormann, J, Glaser, S, Patil, P, de Faria, FW, Richter, M, Verma, A, Balbach, ST, Wagener, R, Bens, S, Dahlum, S, Göbel, C, Münter, D, Inserte, C, Graf, M, Kremer, E, Melcher, V, Di Stefano, G, Santi, R, Chan, A, Dogan, A, Bush, J, Hasselblatt, M, Cheng, S, Spetalen, S, Fosså, A, Hartmann, W, Herbrüggen, H, Robert, S, Oyen, F, Dugas, M, Walter, C, Sandmann, S, Varghese, J, Rossig, C, Schüller, U, Tzankov, A, Pedersen, MB , d'Amore, FA, Mellgren, K, Kontny, U, Kancherla, V, Veloza, L, Missiaglia, E, Fataccioli, V, Gaulard, P, Burkhardt, B, Soehnlein, O, Klapper, W, de Leval, L, Siebert, R & Kerl, K 2024, 'Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas', Nature Communications, vol. 15, no. 1, 8571, pp. 8571. https://doi.org/10.1038/s41467-024-52826-0

Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas. / Fischer, Anja; Albert, Thomas K.; Moreno, Natalia et al.
In: Nature Communications, Vol. 15, No. 1, 8571, 03.10.2024, p. 8571.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas

AU - Fischer, Anja

AU - Albert, Thomas K.

AU - Moreno, Natalia

AU - Interlandi, Marta

AU - Mormann, Jana

AU - Glaser, Selina

AU - Patil, Paurnima

AU - de Faria, Flavia W.

AU - Richter, Mathis

AU - Verma, Archana

AU - Balbach, Sebastian T.

AU - Wagener, Rabea

AU - Bens, Susanne

AU - Dahlum, Sonja

AU - Göbel, Carolin

AU - Münter, Daniel

AU - Inserte, Clara

AU - Graf, Monika

AU - Kremer, Eva

AU - Melcher, Viktoria

AU - Di Stefano, Gioia

AU - Santi, Raffaella

AU - Chan, Alexander

AU - Dogan, Ahmet

AU - Bush, Jonathan

AU - Hasselblatt, Martin

AU - Cheng, Sylvia

AU - Spetalen, Signe

AU - Fosså, Alexander

AU - Hartmann, Wolfgang

AU - Herbrüggen, Heidi

AU - Robert, Stella

AU - Oyen, Florian

AU - Dugas, Martin

AU - Walter, Carolin

AU - Sandmann, Sarah

AU - Varghese, Julian

AU - Rossig, Claudia

AU - Schüller, Ulrich

AU - Tzankov, Alexandar

AU - Pedersen, Martin B.

AU - d'Amore, Francesco A.

AU - Mellgren, Karin

AU - Kontny, Udo

AU - Kancherla, Venkatesh

AU - Veloza, Luis

AU - Missiaglia, Edoardo

AU - Fataccioli, Virginie

AU - Gaulard, Philippe

AU - Burkhardt, Birgit

AU - Soehnlein, Oliver

AU - Klapper, Wolfram

AU - de Leval, Laurence

AU - Siebert, Reiner

AU - Kerl, Kornelius

PY - 2024/10/3

Y1 - 2024/10/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85205605573&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-52826-0

DO - 10.1038/s41467-024-52826-0

M3 - Journal article

C2 - 39362842

AN - SCOPUS:85205605573

SN - 2041-1723

VL - 15

SP - 8571

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8571

ER -

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

Abstract

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