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
; 32(4): 941-951, 2018 04.
Article
em En
| MEDLINE
| ID: mdl-29151585
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.
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Base de dados:
MEDLINE
Assunto principal:
Oncogenes
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Linfócitos T
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Deleção de Sequência
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PTEN Fosfo-Hidrolase
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
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Proteína 1 de Leucemia Linfocítica Aguda de Células T
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article