RESUMO
Peripheral T-cell lymphoma is an aggressive non-Hodgkin's lymphoma characterized by excessive proliferation of transformed mature T cells. The number and nature of genetic aberrations required and sufficient for transformation of normal T cells into lymphomas is unknown. Here, using a combinatorial in vitro-approach, we demonstrate that overexpression of MYC together with activated AKT in conditions of inhibition of intrinsic apoptosis rapidly resulted in transformation of mature mouse T cells with a frequency approaching 100%. Injection of transformed cells into mice resulted in rapid development of aggressive T cell lymphoma, characterized by spread to several organs, destruction of tissue architecture and rapid death of the animals. TcR-sequencing revealed a polyclonal repertoire of tumor cells indicating that co-expression of MYC, activated AKT and BCLXL is sufficient for tumor transformation and do not require acquisition of additional genetic events. When analyzing cells with inducible expression we found that proliferation of transformed T cells required sustained expression of both MYC and AKT. AKT exerted a dual function as it inhibited induction of, and promoted exit from, cellular quiescence and contributed to inhibion of apoptosis. Downregulation of AKT and/or MYC together with BCLXL resulted in rapid and complete elimination of cells through induction of apoptotic cell death.
RESUMO
The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in lambda-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration.