A systems biology approach in understanding oncogenic cooperation between TAL1 expression and PTEN deletion in T-cell acute lymphoblastic leukaemia

T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors. However, how these transcription factors cooperate with oncogenic mutations has been difficult to assess due to a lack of robust T cell model systems. Here we utilize a new ex vivo pro-T cell model to study oncogenic cooperation. Using a systems biological approach we dissect the pro-T cell signaling network driven by interleukin-7, stem cell factor (Scf) and Notch1 and identify downstream Akt, Stat, E2f and Myc genetic signaling networks. Furthermore, we demonstrate that ectopic expression of the TAL1 transcription factor and PTEN deletion are bona-fide cooperating events leading to Scf addiction and metabolic reprogramming, partially through upregulation of the lactate transporter Mct4. This ex vivo pro-T cell system is a powerful new model system to understand transforming events and the identification of new therapeutic targets in T-cell malignancies.