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.

Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Molecular Biotechnology and Health Sciences University of Torino Torino Italy

Department of Pathology Boston Children's Hospital and Harvard Medical School Boston MA USA

Department of Pathology Medical University of Vienna Vienna Austria

Department of Pathology University of Cambridge Cambridge UK

Division of Cell and Developmental Biology Center for Anatomy and Cell Biology Medical University of Vienna Vienna Austria

Division of Hematopathology IEO European Institute of Oncology IRCCS Milan Italy

Division of Immunobiology Institute of Immunology Center for Pathophysiology Infectiology and Immunology Medical University of Vienna Vienna Austria

Faculty of Medicine Masaryk University Brno Czech Republic

Ludwig Boltzmann Institute Applied Diagnostics Vienna Austria

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