Cellular redox homeostasis maintained by malic enzyme 2 is essential for MYC-driven T cell lymphomagenesis

T cell lymphomas (TCLs) are a group of rare and heterogeneous tumors. Although proto-oncogene MYC has an important role in driving T cell lymphomagenesis, whether MYC carries out this function remains poorly understood. Here, we show that malic enzyme 2 (ME2), one of the NADPH-producing enzymes associated with glutamine metabolism, is essential for MYC-driven T cell lymphomagenesis. We establish a CD4-Cre; Myc flox/+transgenic mouse mode, and approximately 90% of these mice develop TCL. Interestingly, knockout of Me2 in Myc transgenic mice almost completely suppresses T cell lymphomagenesis. Mechanistically, by transcriptionally up-regulating ME2, MYC maintains redox homeostasis, thereby increasing its tumori-genicity. Reciprocally, ME2 promotes MYC translation by stimulating mTORC1 activity through adjusting glutamine metabolism. Treatment with rapamycin, an inhibitor of mTORC1, blocks the development of TCL both in vitro and in vivo. Therefore, our findings identify an important role for ME2 in MYC-driven T cell lymphomagenesis and reveal that MYC-ME2 circuit may be an effective target for TCL therapy.

Automated summary

Research reveals that MYC gene plays an important role in driving T cell lymphomagenesis, and malic enzyme 2 (ME2), an enzyme associated with glutamine metabolism, is essential in this process. By establishing a CD4-Cre; Myc flox/+ transgenic mouse model, it is found that knockout of Me2 significantly suppresses T cell lymphomagenesis. Mechanistically, MYC up-regulates ME2 to maintain redox homeostasis, while ME2 stimulates mTORC1 activity through adjusting glutamine metabolism, promoting MYC translation. Overall, these findings highlight the crucial role of ME2 in MYC-driven T cell lymphomagenesis and suggest the MYC-ME2 circuit as a potential target for TCL therapy.