HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy.
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| Title: | HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy. |
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| Authors: | Zrimšek, Maša, Draganić, Kristina, Malzer, Anna, Doblmayr, Verena, Mišura, Katarina, de Freitas E Silva, Rafael, Matthews, Jamie D, Iannelli, Fabio, Wohlhaupter, Sabrina, Pérez Malla, Carlos Uziel, Fischer, Heinz, Schachner, Helga, Schiefer, Ana-Iris, Sheibani-Tezerji, Raheleh, Chiarle, Roberto, Turner, Suzanne Dawn, Ellmeier, Wilfried, Seiser, Christian, Egger, Gerda |
| Publisher Information: | Springer Science and Business Media LLC https://doi.org/10.1038/s41375-025-02584-9 Leukemia 2025-06-03T14:42:21Z 2025-04-02 2024-09-21 2025-06-03T14:42:20Z |
| Document Type: | Electronic Resource |
| Abstract: | Acknowledgements: This research was funded in part by the Austrian Science Fund (FWF) [10.55776/I4066]. For open access purposes, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. CUPM was supported by the Austrian Science Fund (FWF) [10.55776/P32771]. KD was supported by the Austrian Science Fund (FWF) SFB F83 [10.55776/F8300]. GE, SDT, and KM received funding from the European Union’s Horizon 2020 Marie Skłodowska-Curie Innovative Training Networks (ITN-ETN) FANTOM under grant agreement no. 101072735. RC was supported by the National Institute of Health (NIH) grant R01 CA196703-01. We would like to thank Michaela Schlederer for her expertise and help with IHC stainings, Melanie R Hassler, Elisa Redl and Alexandra Zisser for initial help in setting up the mouse models, Astrid Haase for help in the lab, Andrea Alvarez Hernandez for staining the human TMA, Prof. Iris Gratz for fruitful discussions and finally Thomas Krausgruber, Prof. Christoph Bock and the CeMM sequencing facility for sequencing and expertise in ATAC-seq data analysis. Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. Here, we investigated the effects of pharmacological or genetic HDAC inhibition on NPM::ALK positive anaplastic large cell lymphoma (ALCL) development to assess the potential use of HDACi for the treatment of this disease. Short-term systemic pharmacological inhibition of HDACs using the HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM::ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of HDAC1 and HDAC2 enzymes were employed. In sharp contrast, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type-specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development. Nevertheless, systemic pharmacological inhibition of HDACs could still potentially improve current therapeutic outcomes. |
| Index Terms: | Animals, Humans, Mice, Benzamides, Pyridines, Genes, Tumor Suppressor, Lymphoma, Large-Cell, Anaplastic, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Anaplastic Lymphoma Kinase, Article |
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| Availability: | Open access content. Open access content |
| Note: | text/xml application/pdf application/pdf application/pdf English English |
| Other Numbers: | HS1 oai:www.repository.cam.ac.uk:1810/385087 1528765325 |
| Contributing Source: | UNIV OF CAMBRIDGE From OAIster®, provided by the OCLC Cooperative. |
| Accession Number: | edsoai.on1528765325 |
| Database: | OAIster |
Nájsť tento článok vo Web of Science | Abstract: | Acknowledgements: This research was funded in part by the Austrian Science Fund (FWF) [10.55776/I4066]. For open access purposes, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. CUPM was supported by the Austrian Science Fund (FWF) [10.55776/P32771]. KD was supported by the Austrian Science Fund (FWF) SFB F83 [10.55776/F8300]. GE, SDT, and KM received funding from the European Union’s Horizon 2020 Marie Skłodowska-Curie Innovative Training Networks (ITN-ETN) FANTOM under grant agreement no. 101072735. RC was supported by the National Institute of Health (NIH) grant R01 CA196703-01. We would like to thank Michaela Schlederer for her expertise and help with IHC stainings, Melanie R Hassler, Elisa Redl and Alexandra Zisser for initial help in setting up the mouse models, Astrid Haase for help in the lab, Andrea Alvarez Hernandez for staining the human TMA, Prof. Iris Gratz for fruitful discussions and finally Thomas Krausgruber, Prof. Christoph Bock and the CeMM sequencing facility for sequencing and expertise in ATAC-seq data analysis.<br />Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. Here, we investigated the effects of pharmacological or genetic HDAC inhibition on NPM::ALK positive anaplastic large cell lymphoma (ALCL) development to assess the potential use of HDACi for the treatment of this disease. Short-term systemic pharmacological inhibition of HDACs using the HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM::ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of HDAC1 and HDAC2 enzymes were employed. In sharp contrast, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type-specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development. Nevertheless, systemic pharmacological inhibition of HDACs could still potentially improve current therapeutic outcomes. |
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