{"doi":"10.1038/s41375-025-02584-9","title":"HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy","abstract":"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.","journal":"Leukemia","year":2025,"id":518165,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1385123,"name":"Kristina Draganić","orcid":"0000-0002-3351-242X","position":1,"is_corresponding":false},{"id":1385124,"name":"Anna Malzer","orcid":"0000-0002-6891-9377","position":2,"is_corresponding":false},{"id":1385592,"name":"Verena Doblmayr","orcid":null,"position":3,"is_corresponding":false},{"id":1385125,"name":"Katarina Mišura","orcid":"0000-0003-4914-0410","position":4,"is_corresponding":false},{"id":1385126,"name":"Rafael de Freitas e Silva","orcid":"0000-0001-7343-5986","position":5,"is_corresponding":false},{"id":997025,"name":"Jamie D. Matthews","orcid":"0000-0002-2980-8615","position":6,"is_corresponding":false},{"id":626524,"name":"Fabio Iannelli","orcid":"0000-0002-2777-1417","position":7,"is_corresponding":false},{"id":1385593,"name":"Sabrina Wohlhaupter","orcid":null,"position":8,"is_corresponding":false},{"id":1385127,"name":"Carlos Uziel Pérez Malla","orcid":"0000-0003-0057-3223","position":9,"is_corresponding":false},{"id":1385128,"name":"Heinz Fischer","orcid":"0000-0003-1280-0200","position":10,"is_corresponding":false},{"id":1385129,"name":"Helga Schachner","orcid":"0000-0002-7116-530X","position":11,"is_corresponding":false},{"id":1385130,"name":"Ana‐Iris Schiefer","orcid":"0000-0003-3555-8672","position":12,"is_corresponding":false},{"id":1385131,"name":"Raheleh Sheibani‐Tezerji","orcid":"0000-0002-1025-646X","position":13,"is_corresponding":false},{"id":42115,"name":"Roberto Chiarle","orcid":"0000-0003-1564-8531","position":14,"is_corresponding":false},{"id":665172,"name":"Suzanne D. Turner","orcid":"0000-0002-8439-4507","position":15,"is_corresponding":false},{"id":374881,"name":"Wilfried Ellmeier","orcid":"0000-0001-8192-8481","position":16,"is_corresponding":false},{"id":191401,"name":"Christian Seiser","orcid":"0000-0002-7046-9352","position":17,"is_corresponding":false},{"id":1027778,"name":"Gerda Egger","orcid":"0000-0003-2489-155X","position":18,"is_corresponding":false},{"id":948368,"name":"Maša Zrimšek","orcid":"0000-0003-4950-1386","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T02:49:04.756302Z","pmid":"40175628","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}