Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Hematology, ACUTE LYMPHOBLASTIC-LEUKEMIA, GENE-EXPRESSION, LINEAGE, ACTIVATION, SELECTION, NOTCH1, MOUSE, PROLIFERATION, INHIBITION, THYMOCYTES, Animals, Carcinogenesis, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Oncogenes, PTEN Phosphohydrolase, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Sequence Deletion, Signal Transduction, Stem Cells, T-Cell Acute Lymphocytic Leukemia Protein 1, T-Lymphocytes, Transcription Factors, Up-Regulation, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Immunology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

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 (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.