Transformation of mouse T cells requires MYC and AKT activity in conjunction with inhibition of intrinsic apoptosis
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Kari Högstrand1, Stephanie Darmanin1, TachaZi Plym Forshell1 and Alf Grandien1
1Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge, 141 57 Stockholm, Sweden
Alf Grandien, email: email@example.com
Keywords: peripheral T-cell lymphoma; transformation; apoptosis; quiescence; AKT
Received: March 06, 2018 Accepted: March 15, 2018 Published: April 20, 2018
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.
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