Deletion of PTEN selectively in T cell progenitors in the thymus results in the rapid development of aggressive T cell lymphomas in a mouse model for T-ALL. We showed that PTEN-/- T cell lymphoma/leukaemia cells were metabolically active as they readily took up key nutrients. Thus, they had high rates of glucose, glutamine, leucine and transferrin uptake, and expressed constitutively high levels of CD71, the transferrin receptor, and CD98, the System L amino acid transporters. Moreover, PTEN-/- T cell lymphoma/leukaemia cells had high levels of mTORc1 activity. PTEN deletion results in accumulation of PI(3,4,5)P3 and activation of AKT. The present report has addressed whether AKT is the driver of the metabolic changes seen in PTEN-/- T cell lymphoma/leukaemia cells. We showed that PTEN deletion in thymocytes prior to malignant transformation, resulted in a robust activation of AKT but did not cause T cells to increase glucose, glutamine or leucine uptake or activate mTORc1. In this context, we noted that PTEN-/- T cell lymphoma/leukaemia cells but not PTEN-/- non-transformed thymocytes expressed high levels of the transcription factor Hif1α that is required for optimal glucose uptake and glycolysis in normal effector T lymphocytes. We therefore evaluated the importance of Hif1α in T cell lymphomagenesis caused by PTEN deletion. These experiments identified the regulation of Hif1α expression as a critical step in the malignant transformation of PTEN-/- T cell progenitors. They also revealed that the metabolic changes that occur in PTEN-/- T lymphoma/leukaemia cells are not a direct consequence of PI(3,4,5)P3 signalling, but must be mediated by the secondary genetic alterations required for malignant transformation in PTEN-/- T cell progenitors.
|Date of Award||2015|
|Supervisor||Doreen Cantrell (Supervisor)|