Sarcoma sinovial en el perro : 2 casos clínicos

Dos casos de sarcoma sinovial fueron diagnosticados en dos Rottweiler mediante biopsias sinoviales. Se describen los signos clínicos y radiográficos, así como las características histopatológicas del tumor y del líquido sinovial.Two cases of synovial sarcoma were diagnosed in two Rottweilers on the basis of synovial biopsies. Clinical and radiographic signs are described, along with histopathologic features of the tumour and synovial fluid

EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NC that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy are limited. Here, we demonstrated that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4-NUT-regulated genes. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NC cells. CDKN2A was identified as the only gene among all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked tumor growth and prolonged survival of NC-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NC growth