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Amsterdam, Netherlands

Van Steensel B.,Netherlands Cancer Institute
EMBO Journal | Year: 2011

Chromatin is the ensemble of genomic DNA and a large number of proteins. Various genome-wide mapping techniques have begun to reveal that, despite the tremendous complexity, chromatin organization is governed by simple principles. This review discusses the principles that drive the spatial architecture of chromatin, as well as genome-wide-binding patterns of chromatin proteins. © 2011 European Molecular Biology Organization | All Rights Reserved. Source

Schumacher T.N.,Netherlands Cancer Institute | Schreiber R.D.,University of Washington
Science | Year: 2015

The clinical relevance of Tcells in the control of a diverse set of human cancers is now beyond doubt. However, the nature of the antigens that allow the immune system to distinguish cancer cells from noncancer cells has long remained obscure. Recent technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies.These observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance Tcell reactivity against this class of antigens. Source

Bernards R.,Netherlands Cancer Institute
Cell | Year: 2012

Genotype-directed therapy holds great promise for the treatment of cancer, but crosstalk between signaling pathways often confounds simple genotype-drug response relationships. To deliver on the promise of precision medicine, a coordinated effort is needed to make a comprehensive inventory of the many signaling feedback circuits that exist in cancer cells. © 2012 Elsevier Inc. Source

Bickmore W.A.,University of Edinburgh | Van Steensel B.,Netherlands Cancer Institute
Cell | Year: 2013

The architecture of interphase chromosomes is important for the regulation of gene expression and genome maintenance. Chromosomes are linearly segmented into hundreds of domains with different protein compositions. Furthermore, the spatial organization of chromosomes is nonrandom and is characterized by many local and long-range contacts among genes and other sequence elements. A variety of genome-wide mapping techniques have made it possible to chart these properties at high resolution. Combined with microscopy and computational modeling, the results begin to yield a more coherent picture that integrates linear and three-dimensional (3D) views of chromosome organization in relation to gene regulation and other nuclear functions. © 2013 Elsevier Inc. Source

Histone deacetylases (HDACs) are epigenetic erasers of lysine-acetyl marks. Inhibition of HDACs using small molecule inhibitors (HDACi) is a potential strategy in the treatment of various diseases and is approved for treating hematological malignancies. Harnessing the therapeutic potential of HDACi requires knowledge of HDAC-function in vivo. Here, we generated a thymocyte-specific gradient of HDAC-activity using compound conditional knockout mice for Hdac1 and Hdac2. Unexpectedly, gradual loss of HDAC-activity engendered a dosage-dependent accumulation of immature thymocytes and correlated with the incidence and latency of monoclonal lymphoblastic thymic lymphomas. Strikingly, complete ablation of Hdac1 and Hdac2 abrogated lymphomagenesis due to a block in early thymic development. Genomic, biochemical and functional analyses of pre-leukemic thymocytes and tumors revealed a critical role for Hdac1/Hdac2-governed HDAC-activity in regulating a p53-dependent barrier to constrain Myc-overexpressing thymocytes from progressing into lymphomas by regulating Myc-collaborating genes. One Myc-collaborating and p53-suppressing gene, Jdp2, was derepressed in an Hdac1/2-dependent manner and critical for the survival of Jdp2-overexpressing lymphoma cells. Although reduced HDAC-activity facilitates oncogenic transformation in normal cells, resulting tumor cells remain highly dependent on HDAC-activity, indicating that a critical level of Hdac1 and Hdac2 governed HDAC-activity is required for tumor maintenance. Source

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