http://repub.eur.nl/res/aut/18082/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/28473/ 2010-06-01T00:00:00Z Polycomb Repressor Complexes (PRCs) are important regulators of embryogenesis. In embryonic stem (ES) cells many genes that regulate subsequent stages in development are enriched at their promoters for PRC1, PRC2 and Ser 5-phosphorylated RNA Polymerase II (RNAP), and contain domains of 'bivalent' chromatin (enriched for H3K4me3; histone H3 di-or trimethylated at Lys 4 and H3K27me3; histone H3 trimethylated at Lys 27). Loss of individual PRC components in ES cells can lead to gene de-repression and to unscheduled differentiation. Here we show that Jarid2 is a novel subunit of PRC2 that is required for the co-recruitment of PRC1 and RNAP to genes that regulate development in ES cells. Jarid2-deficient ES cells showed reduced H3K4me2/me3 and H3K27me3 marking and PRC1/PRC2 recruitment, and did not efficiently establish Ser 5-phosporylated RNAP at target genes. ES cells lacking Jarid2, in contrast to previously characterized PRC1 and PRC2 mutants, did not inappropriately express PRC2 target genes. Instead, they show a severely compromised capacity for successful differentiation towards neural or mesodermal fates and failed to correctly initiate lineage-specific gene expression in vitro. Collectively, these data indicate that transcriptional priming of bivalent genes in pluripotent ES cells is Jarid2-dependent, and suggests that priming is critical for subsequent multi-lineage differentiation. http://repub.eur.nl/res/pub/15252/ 2008-09-01T00:00:00Z Rationale: The 62005 EORTC phase III trial, comparing two doses of imatinib in patients with advanced GIST, reported a median progression-free survival of 25 months with a trend towards dose dependency for progression-free survival. The current analysis of that study aimed to assess whether histological/immunohistochemical parameters correlate with clinical response to imatinib. Patients and methods: Pre-treatment samples of GISTs from 546 patients enroled in phase III study were analysed for immunohistochemical characteristics, correlations with clinicopathological data, with survival and with tumours' genotype. Results: There was no correlation between immunomorphological or clinical characteristics and response to treatment, PFS or OS. No correlations between immunophenotype of the tumour and PFS or OS in the two dose arms were observed. Conclusions: The results confirm the heterogeneity of GIST in terms of immunophenotypic expression, but indicate that these parameters have no impact on the outcome of the patients under imatinib treatment.