HDAC1 acts as tumor suppressor in ALK-positive anaplastic large-cell lymphoma: Implications for HDAC inhibitor therapy [RNA-Seq]
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. Overall design: We used transgenic mice in which the human oncoprotein NPM-ALK was expressed under the T cell-specific Cd4 promoter.  NPM-ALK mice were further crossed with Cd4-CRE+ mice with floxed exons 6 of the Hdac1 gene, which produced T cell-specific NPM-ALK transgenic mice with an additional Hdac1  knockout (NPM-ALK Hdac1KO). Differential gene expression was done using RNA-sequencing of tumor tissues from biological replicates (n=4) of NPM-ALK versus NPM-ALK Hdac1KO