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T-cell lymphomas in murine in vitro and in vivo models are associated with translocations involving chromosomal band 15D3 or trisomy 15

Proc Amer Assoc Cancer Res, Volume 47, 2006

256 

Introduction: Activation of the oncogene C-MYC has been described in various diseases, e.g. in Burkitt's lymphoma. It can result from different mechanisms, e.g. translocations involving the C-MYC locus on human chromosome 8q24 or the murine chromosome 15D3 or from an increase in the gene dosage. We cytogenetically analyzed two different murine T-cell lymphomas, a N-RAS transgenic mice with and without methyltransferase Suv39h1-deficiency and a cell line resembling the human anaplastic large cell lymphoma (ALCL). T-cell lymphomas of both models analyzed showed different alterations of the c-myc locus on mouse chromosome 15D3. Methods: Chromosome spreads were prepared from T-cells according to standard protocols. Spectral karyotyping (SKY) was carried out according to the manufacturer‘s instructions (Applied Spectral Imaging, Ltd., Migdal HaEmek, Israel). Briefly, metaphase chromosomes were denatured in 70% formamide, 2x SSC for 1.5 min and dehydrated. The mouse SKY probe mixture was denatured at 80°C for 7 min and preannealed at 37°C for 1h. Hybridization took place for 48-72h in a humidified chamber. Image acquisition was performed with the SpectraCube system and the SKY View™ software was utilized for analysis. For fluorescence in situ hybridization (FISH), a probe hybridizing to the c-myc locus on 15D3 was generated from BAC clone RP24-488H15. Results: Nearly all T-cell lymphomas from N-RAS transgenic mice and transgenics with Suv39h1 deficiency showed numerical as well as structural chromosomal alterations. 3 of 4 clones from N-RAS transgenic mice with Suv39h1-deficiency and both clones from N-RAS transgenic mice without Suv39h1-deficiency showed translocations with breakpoints in 15D3. Different regions on chromosomes 6, 11, and 14 were involved as translocation partners, but the genes involved remain unclear. Thus, the methyltransferase deficiency does not seem to result in an enhanced chromosomal instability. SKY analysis of the ALCL cell line TS1G6 showed a complex karyotype with numerical as well as structural chromosomal alterations. Trisomy 15 was found in all 20 metaphases of the ALCL cell line. Conclusion: The numerical and structural alterations of murine chromosome 15 described in both models may induce an activation of the c-myc oncogene. The detailed molecular cytogenetic characterization of these alterations may help to clarify the mechanisms of c-myc activation.