Balanced Epigenetic Regulation of MHC Class I Expression in Tumor Cells by the Histone Ubiquitin Modifiers BAP1 and PCGF1.

MHC class I (MHC-I) molecules are critical for CD8+ T cell responses to viral infections and malignant cells, and tumors can downregulate MHC-I expression to promote immune evasion. In this study, using a genome-wide CRISPR screen on a human melanoma cell line, we identified the polycomb repressive complex 1 (PRC1) subunit PCGF1 and the deubiquitinating enzyme BAP1 as opposite regulators of MHC-I transcription. PCGF1 facilitates deposition of ubiquitin at H2AK119 at the MHC-I promoters to silence MHC-I, whereas BAP1 removes this modification to restore MHC-I expression. PCGF1 is widely expressed in tumors and its depletion increased MHC-I expression in multiple tumor lines, including MHC-Ilow tumors. In cells characterized by poor MHC-I expression, PRC1 and PRC2 act in parallel to impinge low transcription. However, PCGF1 depletion was sufficient to increase MHC-I expression and restore T cell-mediated killing of the tumor cells. Taken together, our data provide an additional layer of regulation of MHC-I expression in tumors: epigenetic silencing by PRC1 subunit PCGF1.

Defibrotide for the treatment of severe hepatic sinusoidal obstruction syndrome: a single-centre experience.

OBJECTIVES: Determine the effectiveness and cost of defibrotide in patients with severe hepatic sinusoidal obstruction syndrome following haematopoietic stem cell transplantation in a tertiary hospital. METHODS: A retrospective observational study. Adults or children treated with defibrotide at a mean dose of 6.8 mg/kg every 6 hours, until the total bilirubin levels are normalised, were included. Main endpoint was complete response, defined as normalised total serum bilirubin levels and resolution of multiple organ failure. Secondary endpoints were survival by 100 days post-transplant, influence of risks factors in effectiveness and cost of treatment. RESULTS: 51 patients (36 adults and 15 children) received defibrotide; median dose of defibrotide administered was 25.19 mg/kg/day (10.0-100.3). Complete response was achieved in 19 (37.3%) patients. By 100 days post-transplant complete response was achieved in 18 (35.3%) patients and the survival rate was 29 (56.9%) patients. There were no significant differences in effectiveness between adults versus paediatrics and between patients who presented risk factors. The mean cost of treatment per patient was €32 916, mean costs in adults was €104 292 and €17 394 in children. CONCLUSION: Regarding the results of our study, it is convenient to identify the patients who will be able to benefit from this treatment according to clinical conditions, medical history and prognosis. Given the great economic impact of defibrotide, we consider that more cost-effectiveness studies are required. TRIAL REGISTRATION NUMBER: EPA-OD, number LBM-DEF-2016-01.