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HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy

M. Zrimšek, K. Draganić, A. Malzer, V. Doblmayr, K. Mišura, R. de Freitas E Silva, JD. Matthews, F. Iannelli, S. Wohlhaupter, CU. Pérez Malla, H. Fischer, H. Schachner, AI. Schiefer, R. Sheibani-Tezerji, R. Chiarle, SD. Turner, W. Ellmeier, C....

. 2025 ; 39 (6) : 1412-1424. [pub] 20250402

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25015505

Grantová podpora
R01 CA196703-01 Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
R01 CA196703 NCI NIH HHS - United States
10.55776/P32771 Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
101072735 EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
10.55776/F8300 Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
32771 Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
I 4066 Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
SFB F83 Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
10.55776/I4066 Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)

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.

Citace poskytuje Crossref.org

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$a 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.
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