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HDAC1 acts as tumor suppressor in ALK-positive anaplastic large-cell lymphoma: Implications for HDAC inhibitor therapy [ATAC-Seq]

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 genetic or pharmacological HDAC inhibition on NPM-ALK positive anaplastic large cell lymphoma (ALCL) development to elucidate potential contraindications or indications for the use of HDACi for the treatment of this rare T-cell lymphoma. Short-term systemic pharmacological inhibition of HDACs using the class I-specific 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 highly homologous class I HDAC1 and HDAC2 enzymes were employed. In sharp contrast to the systemic inhibition, 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. The accelerated lymphomagenesis primarily depended on the enzymatic activity of HDAC1, as the expression of a catalytically inactive HDAC1 protein showed similar effects to the complete knockout. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development, however systemic pharmacological inhibition of HDACs is still a valid treatment strategy, which could potentially improve current therapeutic outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE271908 | GEO | 2025/06/16

REPOSITORIES: GEO

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Project description:Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from DSS-induced murine colitis. While tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal Disease Activity Index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation Total RNAs from the colon of three control and three Hdac2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).

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HDAC1 acts as tumor suppressor in ALK-positive anaplastic large-cell lymphoma: Implications for HDAC inhibitor therapy [ATAC-Seq]

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