Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T cell model system

T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors in developing T cells. However, the molecular basis underlying cooperation between transcription factor expression and additional oncogenic mutations in driving T-ALL has been difficult to assess due to limited 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 first dissect the pro-T cell signaling network driven by interleukin-7 (Il7), stem cell factor (Scf) and Notch1 and identify key downstream Akt, Stat, E2f and Myc genetic signaling networks. Next, this pro-T cell system was used to demonstrate that ectopic expression of the TAL1 transcription factor and Pten deletion are bona-fide cooperating events resulting in an increased stem-cell signature, upregulation of a specific E2f signaling network and metabolic reprogramming with higher influx of glucose carbons into the TCA cycle. This ex vivo pro-T cell system thereby provides a powerful new model system to investigate how normal T cell signaling networks are perturbed and/or hijacked by different oncogenic events found in T-ALL.Leukemia accepted article preview online, 20 November 2017. doi:10.1038/leu.2017.328.

Publication year:2018

BOF-keylabel:yes

IOF-keylabel:yes

BOF-publication weight:6

CSS-citation score:1

Authors from:Government, Higher Education

Accessibility:Open