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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\n                    <jats:italic>Hdac1<\/jats:italic>\n                    or\n                    <jats:italic>Hdac2<\/jats:italic>\n                    in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with\n                    <jats:italic>Hdac1<\/jats:italic>\n                    loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that\n                    <jats:italic>Hdac1<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02584-9","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T14:24:03Z","timestamp":1743776643000},"page":"1412-1424","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large\u00a0cell lymphoma: implications for HDAC inhibitor therapy"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4950-1386","authenticated-orcid":false,"given":"Ma\u0161a","family":"Zrim\u0161ek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Dragani\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Malzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Doblmayr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Mi\u0161ura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"de Freitas E Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie D.","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Iannelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Wohlhaupter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Uziel","family":"P\u00e9rez Malla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Schachner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3555-8672","authenticated-orcid":false,"given":"Ana-Iris","family":"Schiefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raheleh","family":"Sheibani-Tezerji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-8531","authenticated-orcid":false,"given":"Roberto","family":"Chiarle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8439-4507","authenticated-orcid":false,"given":"Suzanne Dawn","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfried","family":"Ellmeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Seiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2489-155X","authenticated-orcid":false,"given":"Gerda","family":"Egger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"key":"2584_CR1","doi-asserted-by":"publisher","first-page":"3681","DOI":"10.1182\/blood.V96.12.3681","volume":"96","author":"H Stein","year":"2000","unstructured":"Stein H, Foss HD, D\u00fcrkop H, Marafioti T, Delsol G, Pulford K, et al. 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