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Early T-cell Precursor ALL (ETP-ALL) is a subgroup of acute T leukemias with a peculiar immunophenotypic profile. Patients display a poor early response to conventional induction treatment, but an outcome after intensified therapy not worse than the other T-ALL. ETP-ALL was extensively characterized from a genetic point of view in the paper published by Zhang et al in 2012, but information about proteomic aberrancies is still lacking. In this study we profiled, by Reverse Phase Protein Arrays, the activation and expression of a considerable number of proteins in a significative cohort of 16 pediatric patients affected by ETP-ALL at diagnosis. We compared protein activation in these patients versus a group of 62 other T-ALL pediatric patients. Phosphoprotemic data were also related to mutational status of ETP-ALL patients. Our most interesting findings concern the hyperactivation of the LCK/Calcineurin and mTOR/STAT3 signaling pathways in ETP-ALL patients. LCK, despite of a lower expression, resulted strikingly boosted in these patients with a concomitant overexpression of the downstream target Calcineurin. The LCK/Calcineurin axis, followed by the activation of the NFAT family of transcription factors, was already demonstrated to be critical for T cell leukemogenesis. We also observed a possible feedback loop which could sustain mTOR activation through p70 S6Kinase hyperphosphorylation. mTOR, in turn, phosphorylates and activates STAT3, counteracting cell differentiation. The mTOR/STAT3 axis activity thus could sustain cell proliferation and survival while maintaining the markedly undifferentiated phenotype typical of ETP-ALL. Interestingly, the activation of the mTOR/STAT3 pathways is not influenced by the presence of FLT3 or PTEN mutations. Our paper also reports in ETP-ALL patients the hyperactivation of the RAS/MAPK and the JAK/STAT signaling pathways, that is not dependant from BRAF, NRAS, IL7R, JAK1 or JAK3 somatic mutations.\udIn conclusion, our study is the first one investigating the activation of a such number of proteins in a wide cohort of pediatric ETP-ALL patients. We identified the specific activation of signaling pathways, such as the LCK/Calcineurin and the mTOR/STAT3 ones, important for T cell leukemogenesis and for the support of cancer cell viability and block of differentiation. Our results will help to explain the mechanism responsible of the poor response to conventional treatment of these patients, and might also suggest new druggable targets for personalized and less toxic therapies

Phosphoproteomic analysis reveals hyperactivation of mTOR/STAT3 and LCK/Calcineurin axes in pediatric early T-cell precursor ALL