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Leukemia. 2018 Apr;32(4):941-951. doi: 10.1038/leu.2017.328. Epub 2017 Nov 20.

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

Author information

1
KU Leuven Center for Human Genetics, Leuven, Belgium.
2
VIB Center for Cancer Biology, Leuven, Belgium.
3
VIB Metabolomics Expertise Center, Leuven, Belgium.
4
VIB Center for Neurobiology & Disease, Leuven, Belgium.

Abstract

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, stem cell factor 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 tricarboxylic acid 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.

PMID:
29151585
PMCID:
PMC5886055
DOI:
10.1038/leu.2017.328
[Indexed for MEDLINE]
Free PMC Article

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