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Tumor model-specific proviral insertional mutagenesis of the Fos/Jdp2/Batf locus
M H Rasmussen1, A B Sørensen, D W Morris
1Department of Molecular Biology, University of Aarhus, C. F. Mollers Allé, Building 130, DK-8000 Aarhus C, Denmark.
Abstract:
Retroviral activation of the AP-1/ATF super family member Jdp2 was recently reported to be a common event in M-MLV-induced T cell lymphoma in p27-null C57x129 mice as compared to wild type-inoculated mice but has not been found important in other models. On the basis of retroviral tag retrieval from 1190 individual Akv- and SL3-3-induced lymphomas, we here report that insertional mutagenesis into the 250-kb Fos/Jdp2/Batf locus is associated with SL3-3 MLV-induced T but not Akv-induced B cell lymphomas of NMRI and SWR mice. Integration pattern and clonality analyses suggest that Jdp2 participates in SL3-3-induced tumorigenesis distinctly as compared to the M-MLV setting. Northern blot analysis showed Jdp2 to be alternatively spliced in various normal tissues as well as MLV-induced lymphomas. Interestingly, in some tumors, proviral insertion seems to activate different mRNA sub-species. Whereas elevated mRNA levels of the Fos gene could not be correlated with provirus presence, in one case, Northern blot analysis as well as quantitative real-time PCR indicated proviral activation of the AP-1 super family member Batf, a gene not previously reported to be a target of insertional mutagenesis. A novel integration cluster between Jdp2 and Batf apparently did not influence the expression level of either gene, underscoring the importance of addressing expression effects to identify target genes of insertion. Altogether, such distinct insertion patterns point to different mechanism of activation of specific proto-oncogenes and are consequently of importance for the understanding of proviral activation mechanisms as well as the specific role of individual oncogenes in tumor development.
Insights
Retroviral insertions target the Fos/Jdp2/Batf locus in specific T cell lymphomas, revealing distinct oncogene activation mechanisms. This study highlights the importance of Jdp2 and Batf in distinct retroviral oncogenesis models.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Retroviral insertional mutagenesis is a key mechanism in oncogenesis.
- Jdp2 (Jun dimerization partner 2) activation by Moloney Murine Leukemia Virus (M-MLV) was previously linked to T cell lymphoma in specific mouse models.
- The role of Jdp2 and related AP-1/ATF family members in other retroviral oncogenesis models remained unclear.
Purpose of the Study:
- To investigate the role of the Fos/Jdp2/Batf locus in Akv- and SL3-3 Murine Leukemia Virus (MLV)-induced lymphomas.
- To compare the insertional mutagenesis patterns and oncogenic roles of Jdp2 and Batf in different MLV-induced tumor types.
- To elucidate the distinct mechanisms of proto-oncogene activation by insertional mutagenesis.
Main Methods:
- Retroviral tag retrieval and analysis of 1190 Akv- and SL3-3 MLV-induced lymphomas.
- Integration pattern and clonality analyses.
- Northern blot analysis and quantitative real-time PCR to assess gene expression and alternative splicing.
Main Results:
- Insertional mutagenesis within the Fos/Jdp2/Batf locus was significantly associated with SL3-3 MLV-induced T cell lymphomas, but not Akv-induced B cell lymphomas.
- Integration patterns suggested a distinct role for Jdp2 in SL3-3 MLV tumorigenesis compared to M-MLV.
- Proviral activation of Batf (Basic leucine zipper transcription factor, ATF-activating transcription factor), a novel target gene, was observed in one tumor.
- Alternative splicing of Jdp2 was detected in normal tissues and MLV-induced lymphomas, with some tumors showing activation of different mRNA splice variants.
Conclusions:
- The Fos/Jdp2/Batf locus is a target for insertional mutagenesis in SL3-3 MLV-induced T cell lymphomas, indicating specific oncogenic pathways.
- Jdp2 and Batf play distinct roles in different MLV-induced oncogenesis models, highlighting context-dependent proto-oncogene activation.
- Understanding these distinct insertion patterns is crucial for deciphering retroviral activation mechanisms and the specific roles of oncogenes in tumor development.
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