Comment[ArrayExpressAccession] E-GEOD-43407 MAGE-TAB Version 1.1 Public Release Date 2013-01-11 Investigation Title Dosage dependent tumor suppression by histone deacetylase 1 and 2 by regulation of Myc collaborating genes and p53 function Comment[Submitted Name] Dosage dependent tumor suppression by histone deacetylase 1 and 2 by regulation of Myc collaborating genes and p53 function Experiment Description comparative genome hybridisation of Hdac1/2 cKO lymphomas and matched normal tissue 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. genomic DNA from LckCre+;Hdac1/2 cKO lymphomas and matched normal genomic DNA was hybridized onto a Nimblegen whole genome array Term Source Name ArrayExpress EFO Term Source File http://www.ebi.ac.uk/arrayexpress/ http://www.ebi.ac.uk/efo/efo.owl Person Last Name Dannenberg Heideman Wilting Yanover Velds de Jong Kerkhoven Jacobs Wessels Dannenberg Person First Name Jan-Hermen Marinus Roel Eva Arno Johann Ron Heinz Lodewyk Jan-Hermen Person Mid Initials R H M F Person Email j.dannenberg@nki.nl Person Affiliation Antoni van Leeuwenhoek hospital Person Address Antoni van Leeuwenhoek hospital, Plesmanlaan 121, Amsterdam, N-Holland, Netherlands Person Roles submitter Protocol Name P-GSE43407-1 P-GSE43407-5 P-GSE43407-4 P-GSE43407-2 P-GSE43407-3 P-GSE43407-6 Protocol Description ID_REF = VALUE = log2FC ratio Cy3/Cy5 Agilent Scanner (model G2505B) at a resolution of 2 micron double pass at 100% PMT for both channels Nimblegen protocol for mouse CGH 12x135 K whole genome tiling array genomic DNA was isolated from approx. 100 mg lymphoma tissue and corresponding normal tail tissue using the Puregene genomic DNA isolation kit from Qiagen Dual Color labeling kit from Nimblegen Background correction and normalization was performed in the NimbleScan program according to manufacturer's protocol; probe annotation and corrected log2 ratios were imported into the R programming language from the NimbleScan output. Protocol Type bioassay_data_transformation image_aquisition hybridization nucleic_acid_extraction labeling feature_extraction Experimental Factor Name ORGANISM PART Experimental Factor Type organism part Comment[SecondaryAccession] GSE43407 Comment[GEOReleaseDate] 2013-01-11 Comment[ArrayExpressSubmissionDate] 2013-01-10 Comment[GEOLastUpdateDate] 2013-01-13 Comment[AEExperimentType] comparative genomic hybridization by array SDRF File E-GEOD-43407.sdrf.txt