Oncogenic cooperation in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, characterized by high white blood cell counts and infiltration of immature T cells into the bone marrow and other tissues. The management of T-ALL involves chemotherapy treatment, which is not specifically targeting leukemic cells. Thus, current treatments are associated with severe side effects for T-ALL patients. Gaining more insight into the mechanism of T-ALL development will be critical for the development of new targeted therapeutic agents, tailored to specific mutations present in the leukemia cells. Recent clinical sequencing studies showed that T-ALL is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors in developing T cells. However, dissecting the molecular mechanism of 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 (IL-7), 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. As a next step, we aimed to assess the potential of IL7R mutations to transform pro-T cells to IL-7 independent growth. We demonstrated that IL7R mutations are weak activators of the Stat5 signaling pathway and only cysteine inserting mutations in the IL7R lead to cell transformation and IL-7 independency. However, aberrant expression of TLX1, which frequently co-occurs with IL7R mutations in T-ALL patients, lowered the threshold requirement for phospho-Stat5. TLX1 bound directly to Stat5 target genes and induced a similar geneset as Stat5. 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.nrpages: 164status: publishe