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Mouse mammary tumor virus with rearranged long terminal repeats causes murine lymphomas
S Yanagawa1, K Kakimi, H Tanaka
1Department of Viral Oncology, Faculty of Medicine, Kyoto University, Japan.
Abstract:
Mouse mammary tumor virus (MMTV) is a slowly transforming retrovirus associated primarily with the induction of mammary tumors. It is widely accepted that T-cell lymphomas of various mouse strains are associated with extra proviruses of MMTV. These extra proviruses showed site-specific rearrangements in the U3 region of long terminal repeats (LTRs), consisting of about 400 nucleotide deletions and occasional substitution resulting in unique tandem repeats. However, the question of whether these mutant MMTVs cause lymphomas has not been experimentally resolved. Here we present distinct evidence that they do. We constructed chimeric MMTVs by replacing the LTR of the recently constructed pathogenic MMTV provirus clone with rearranged LTRs of MMTV proviruses obtained from two DBA/2 mouse lymphoma cell lines, MLA and DL-8, and inoculated them into BALB/c mice. These mice developed lymphomas, but no mammary tumors, 4 to 11 months postinoculation, whereas the original pathogenic MMTV clone alone induced mammary tumors. These results showed that the tissue specificity of MMTV tumorigenesis is determined by the LTR structures.
Insights
Mutant mouse mammary tumor virus (MMTV) with rearranged long terminal repeats (LTRs) cause T-cell lymphomas in mice. These findings demonstrate that MMTV LTR structure dictates tissue-specific tumor development.
Area of Science:
- Virology
- Oncology
- Genetics
Background:
- Mouse mammary tumor virus (MMTV) is a retrovirus linked to mammary tumors.
- Extrachromosomal MMTV proviruses with rearranged long terminal repeats (LTRs) are associated with T-cell lymphomas.
- The causal role of these rearranged MMTVs in lymphoma induction remained unproven.
Purpose of the Study:
- To experimentally determine if rearranged MMTV proviruses can induce lymphomas.
- To investigate the role of MMTV LTR structure in determining tumor tissue specificity.
Main Methods:
- Constructed chimeric MMTV by replacing the LTR of a pathogenic MMTV clone with rearranged LTRs from lymphoma-derived MMTV.
- Inoculated chimeric MMTVs into BALB/c mice.
- Monitored mice for tumor development (mammary tumors and lymphomas).
Main Results:
- Mice inoculated with chimeric MMTVs developed lymphomas but not mammary tumors.
- Control mice inoculated with the original pathogenic MMTV clone developed mammary tumors.
- The development of lymphomas was observed 4 to 11 months post-inoculation.
Conclusions:
- Rearranged MMTV LTR structures are directly implicated in causing T-cell lymphomas.
- MMTV LTR structure is the critical determinant of tissue-specific tumorigenesis.
- This study provides experimental evidence linking specific MMTV variants to distinct cancer types.