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N-myc is frequently activated by proviral insertion in MuLV-induced T cell lymphomas
M van Lohuizen1, M Breuer, A Berns
1Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam.
Abstract:
We report a new common proviral insertion site in murine leukemia virus-induced T cell lymphomas to be N-myc. Proviral activation of N-myc was found in 35% of independently induced primary tumors. The vast majority of the proviral insertions occur within a small segment of the 3'-untranslated region of the N-myc gene, directly downstream of the protein-encoding domain. This results in an increased level of expression of a truncated N-myc mRNA. Together with the previously shown c-myc activation we now find involvement of myc genes in greater than 75% of the primary T cell lymphomas induced by Moloney murine leukemia virus in C57BL10 and BALB/c mice, and show for the first time that N-myc can be over-expressed by a mechanism other than gene amplification.
Insights
Murine leukemia virus activates the N-myc gene in T cell lymphomas, with insertions in the 3'-untranslated region leading to increased truncated N-myc mRNA. This finding, alongside c-myc activation, implicates myc genes in over 75% of these lymphomas.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Murine leukemia virus (MLV) is known to induce T cell lymphomas.
- Activation of the c-myc gene has been previously identified as a common event in MLV-induced lymphomas.
Purpose of the Study:
- To identify novel common proviral insertion sites in MLV-induced T cell lymphomas.
- To investigate the role of N-myc in the pathogenesis of these lymphomas.
Main Methods:
- Analysis of proviral insertion sites in Moloney murine leukemia virus-induced T cell lymphomas in mice.
- Quantification of N-myc mRNA expression levels.
Main Results:
- N-myc was identified as a new common proviral insertion site, activated in 35% of primary tumors.
- Proviral insertions occurred in the 3 -untranslated region of N-myc, leading to overexpression of a truncated N-myc mRNA.
- Combined with c-myc activation, myc gene involvement was found in over 75% of lymphomas.
Conclusions:
- N-myc can be activated by proviral insertion in MLV-induced T cell lymphomas.
- This mechanism leads to overexpression of N-myc through a truncated mRNA, distinct from gene amplification.
- Myc gene family members (c-myc and N-myc) are critically involved in the majority of MLV-induced T cell lymphomas.