Complex lymphoid and epithelial thymic tumours in Thyl-myc transgenic mice

Abstract

T-lymphocyte development takes place mainly in the thymus, where stromal cells of epithelial and haemopoietic origin are involved in inductive and selective mechanisms, which enable specific lymphocyte populations to migrate to the periphery and establish a network of immune responses. Experiments with intact animals have clarified the precursor-product relationships between thymocyte subpopulations, but the molecular mechanisms of cell interactions in the thymus are difficult to study in vivo. In an attempt to expand thymic cell populations in vivo and maintain them in vitro for such studies, we directed high levels of expression of the murine c-myc proto-oncogene in transgenic mice by inserting it into the mouse Thy-1 transcriptional unit. Such mice develop thymic tumours which contain proliferating thymocytes and, interestingly, expanded populations of epithelial cells. Both cell types can be maintained in vitro.

Reversible activation of c-Myc in thymocytes enhances positive selection and induces proliferation and apoptosis in vitro

“…So far using conventional transgenic mouse technology dierent c-myc transgenic mice have been generated by targeting expression of the c-myc transgene to the lymphoid compartment (CD2-c-myc,Thy1-c-myc, Em-cmyc) (Stewart et al, 1993;Spanopoulou et al, 1989;Adams et al, 1985). However, classical transgenic technology suers from the limitation that the transgene in question is placed under the control of a tissue-speci®c regulatory element that is normally expressed throughout the ontogeny of an organism.…”

“…The enhanced eciency of positive selection caused by c-Myc activation might have an impact on the development of clonal thymic tumors observed in c-myc transgenic mice. In Thy1-and CD2-c-myc transgenic mice, thymic tumours that arise exhibit predominantly a double positive phenotype (Spanopoulou et al, 1989;Stewart et al, 1993) suggesting that the sensitivity to c-myc transformation may be restricted to a certain window during their development of T cells.…”

“…In the case of all transgenic mice where c-myc is expressed in the lymphoid compartment, constitutive deregulated c-myc expression resulted in the formation of tumours which made it dicult to analyse these mice. Tumours are of a clonal nature, arising rapidly after birth (Stewart et al, 1993;Adams et al, 1985;Spanopoulou et al, 1989).…”

“…Since proliferation, dierentiation and apoptosis play such crucial roles in T cell development, the thymus presents itself as a particularly informative experimental system in which to analyse the consequences of c-Myc activation in vivo. To date, conventional transgenic technology has been used to target c-myc expression to lymphocytes (CD2-c-myc, Thy1-c-myc, Em-c-myc) (Stewart et al, 1993;Spanopoulou et al, 1989;Adams et al, 1985). However, all these studies suer from the limitation of classical transgenic technology in that the transgene in question is placed under the control of a tissue-speci®c regulatory element that is typically expressed throughout the ontogeny of an organ or tissue.…”

Rapid induction of B-cell lymphomas in mice carrying a human IgH/c-mycYAC

“…The translocated and often mutated c-myc gene is expressed and deregulated at various levels ± these include alternative promoters, transcription elongation and mRNA stability ± whereas the non-translocated allele is usually transcriptionally silent (Spencer and Groudine, 1991). Exogenous expression of c-myc in transgenic mice can induce di erent types of neoplastic proliferation depending on promoter/enhancer combinations which drive transgene expression (Stewart et al, 1984;Spanopoulou et al, 1989;Sandgren et al, 1991). Lymphoid tumors have been found in mice carrying various minigene constructs with c-myc under the control of a murine or human IgH intron enhancer (Adams et al, 1985;Suda et al, 1987;Schmidt et al, 1988;Yukawa et al, 1989).…”