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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Mar 07, 2013 |
| Title |
Genetic and transcriptome analyses of early T-cell checkpoint failure and leukemia initiation in Rag1-deficient NOD mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Both immunodeficient and wild type NOD mice exhibit defects in control of early T-cell development in the thymus. We show that Rag1-deficient NOD mice fail to enforce both the b-selection checkpoint and an earlier T-cell commitment checkpoint, based on genome-wide genetic and transcriptome analyses. A major QTL peak for the checkpoint breakthrough phenotype mapped to the diabetes susceptibility Idd9/11 region, as confirmed by congenic mouse analysis. Genome-wide RNA deep-sequencing revealed two classes of differences between NOD and B6 Rag1-deficient thymocytes: first, effects of genetic background prior to breakthrough, and second, effects of the breakthrough itself. These genotypes differentially express numerous signal transduction genes, prominently tyrosine kinase and actin-binding genes, some located within QTL regions. Emerging NOD breakthrough cells depart from the expected DN3 phenotype by expressing many stem cell-associated proto-oncogenes, such as Lmo2, Hhex, Lyl1, and Kit which are normally repressed earlier, and by illegitimate activation of post-b-selection genes like Cd2, Cd5, and Cd4. Co-expression of stem cell and T-cell genes persists in thymic lymphoma cells that emerge with high penetrance in these mice. These results imply that NOD thymocytes have defects that can collapse regulatory boundaries at two early T-cell checkpoints, which may predispose them to leukemia and autoimmunity.
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| Overall design |
Genetic and transcriptome analyses of early T-cell checkpoint failure and leukemia initiation in Rag1-deficient NOD mice
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| Contributor(s) |
Yui MA, Feng N, Zhang JA, Liaw CY, Rothenberg EV |
| Citation(s) |
23440410 |
| Submission date |
Sep 07, 2012 |
| Last update date |
May 15, 2019 |
| Contact name |
Mary Yui |
| E-mail(s) |
yui@caltech.edu, jingli@caltech.edu
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| Organization name |
California Institute of Technology
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| Department |
Biology
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| Lab |
Rothenberg
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| Street address |
1200 E California Blvd
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| City |
Pasadena |
| ZIP/Postal code |
91125 |
| Country |
USA |
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| Platforms (1) |
| GPL9250 |
Illumina Genome Analyzer II (Mus musculus) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA174611 |
| SRA |
SRP015484 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE40688_RAW.tar |
1.5 Mb |
(http)(custom) |
TAR (of RPKM) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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