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Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system.
Leukemia ( IF 11.4 ) Pub Date : 2018-Apr-01 , DOI: 10.1038/leu.2017.328
S Bornschein , S Demeyer , R Stirparo , O Gielen , C Vicente , E Geerdens , B Ghesquière , S Aerts , J Cools , C E de Bock

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.

中文翻译:

使用新型pro-T细胞模型系统,定义T-ALL中TAL1表达与Pten缺失之间致癌合作的分子基础。

T细胞急性淋巴细胞白血病(T-ALL)是由发育中的T细胞中多种突变的积累与转录因子的异位表达相结合引起的。然而,由于有限的健壮的T细胞模型系统,难以评估转录因子表达与其他致癌突变在驱动T-ALL之间协同作用的分子基础。在这里,我们利用新的离体前T细胞模型来研究致癌合作。我们首先使用系统生物学方法解剖由白介素7,干细胞因子和Notch1驱动的pro-T细胞信号网络,并确定关键的下游Akt,Stat,E2f和Myc基因信号网络。下一个,此pro-T细胞系统用于证明TAL1转录因子的异位表达和Pten缺失是真正的合作事件,导致干细胞签名增加,特异性E2f信号网络上调和代谢重编程以及更高的内源性葡萄糖碳进入三羧酸循环。因此,该离体前T细胞系统提供了一个功能强大的新模型系统,以研究正常的T细胞信号网络如何受到T-ALL中发现的不同致癌事件的干扰和/或劫持。
更新日期:2017-11-20
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