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| Status |
Public on Jan 11, 2013 |
| Title |
Dosage dependent tumor suppression by histone deacetylase 1 and 2 by regulation of Myc collaborating genes and p53 function |
| Organism |
Mus musculus |
| Experiment type |
Genome variation profiling by genome tiling array
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| Summary |
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.
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| Overall design |
genomic DNA from LckCre+;Hdac1/2 cKO lymphomas and matched normal genomic DNA was hybridized onto a Nimblegen whole genome array
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| Contributor(s) |
Heideman MR, Wilting RH, Yanover E, Velds A, de Jong J, Kerkhoven RM, Jacobs H, Wessels LF, Dannenberg J |
| Citation(s) |
23327920 |
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| Submission date |
Jan 10, 2013 |
| Last update date |
Apr 05, 2013 |
| Contact name |
Jan-Hermen Dannenberg |
| E-mail(s) |
j.dannenberg@nki.nl
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| Organization name |
Antoni van Leeuwenhoek hospital
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| Street address |
Plesmanlaan 121
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| City |
Amsterdam |
| State/province |
N-Holland |
| ZIP/Postal code |
1066 CX |
| Country |
Netherlands |
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| Platforms (1) |
| GPL13924 |
Nimblegen 12-plex 135K full genome mouse custom NKI array [091016_MM9_RK_CGH_HX12] |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA185991 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE43407_RAW.tar |
74.5 Mb |
(http)(custom) |
TAR (of PAIR, TXT) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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