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.

• MeSH
• Anaplastic Lymphoma Kinase * metabolism   genetics   MeSH
• Lymphoma, Large-Cell, Anaplastic * drug therapy   pathology   genetics   metabolism   MeSH
• Benzamides pharmacology   MeSH
• Histone Deacetylase 1 * genetics   antagonists & inhibitors   physiology   metabolism   MeSH
• Histone Deacetylase 2 genetics   MeSH
• Histone Deacetylase Inhibitors * pharmacology   therapeutic use   MeSH
• Humans MeSH
• Mice MeSH
• Pyridines pharmacology   MeSH
• Genes, Tumor Suppressor * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alk protein, mouse MeSH Browser
• Anaplastic Lymphoma Kinase * MeSH
• Benzamides MeSH
• entinostat MeSH Browser
• Hdac1 protein, mouse MeSH Browser
• Histone Deacetylase 1 * MeSH
• Histone Deacetylase 2 MeSH
• Histone Deacetylase Inhibitors * MeSH
• Pyridines MeSH