HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy
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.
Authors
- Christian Seiser (ORCID: https://orcid.org/0000-0002-7046-9352)
- Jamie D. Matthews (ORCID: https://orcid.org/0000-0002-2980-8615)
- Rafael de Freitas e Silva (ORCID: https://orcid.org/0000-0001-7343-5986)
- Katarina Mišura (ORCID: https://orcid.org/0000-0003-4914-0410)
- Wilfried Ellmeier (ORCID: https://orcid.org/0000-0001-8192-8481)
- Roberto Chiarle (ORCID: https://orcid.org/0000-0003-1564-8531)
- Ana‐Iris Schiefer (ORCID: https://orcid.org/0000-0003-3555-8672)
- Fabio Iannelli (ORCID: https://orcid.org/0000-0002-2777-1417)
- Carlos Uziel Pérez Malla (ORCID: https://orcid.org/0000-0003-0057-3223)
- Maša Zrimšek (ORCID: https://orcid.org/0000-0003-4950-1386)
- Kristina Draganić (ORCID: https://orcid.org/0000-0002-3351-242X)
- Raheleh Sheibani‐Tezerji (ORCID: https://orcid.org/0000-0002-1025-646X)
- Suzanne Dawn Turner (ORCID: https://orcid.org/0000-0002-8439-4507)
- Heinz Fischer (ORCID: https://orcid.org/0000-0003-1280-0200)
- Sabrina Wohlhaupter
- Gerda Egger (ORCID: https://orcid.org/0000-0003-2489-155X)
- Anna Malzer (ORCID: https://orcid.org/0000-0002-6891-9377)
- Helga Schachner (ORCID: https://orcid.org/0000-0002-7116-530X)
- Verena Doblmayr
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- Masaryk University (CZ)
- University of Cambridge (GB)
- Comprehensive Cancer Center Vienna (AT)
- Ludwig Boltzmann Institute Applied Diagnostics (AT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Turin (IT)
- European Institute of Oncology (IT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Leukemia
- Published
- 2025-04-02
- DOI
- https://doi.org/10.1038/s41375-025-02584-9
- Citations
- 3
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Foundation for the National Institutes of Health
- European Commission
- Austrian Science Fund
- Universität Wien
- Medizinische Universität Wien
- National Institutes of Health
- Horizon 2020 Framework Programme