Ferrata Storti Foundation, Haematologica, 10(99), p. e188-e192
DOI: 10.3324/haematol.2014.104992
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Brief Summary Precursor T-cell acute lymphoblastic leukemia represents one of the major challenges of pediatric oncology, because relapses are frequently fatal and the molecular understanding of leukemogenesis and maintenance is limited in this entity. Here, we aimed at identifying novel leukemogenic driver mutations and first analyzed trios of bone marrow DNA of 5 patients with T-cell acute lymphoblastic leukemia obtained at initial diagnosis, remission and relapse by whole exome sequencing. We identified a recurrent, leukemia-specific mutation resulting in a N642H amino acid substitution in the SH2-domain of STAT5B. We subsequently validated these results by sequencing the entire STAT5B gene in two independent large cohorts of patients and identified this mutation in 17 of 301 patients (6.3%) with primary T-cell acute lymphoblastic leukemia recruited from the ALL-BFM 2000 trial and in 7 of 78 relapsed T-cell acute lymphoblastic leukemia patients (9.0%) from the BFM-ALL-REZ trials. The analysis of clinical data revealed that the presence of this mutation was associated with a significantly increased risk of relapse (RR 2.47, p=0.038). Cell based assays in transduced BaF3 cells and in xenografted leukemic cells showed this mutation to confer constitutive STAT5 phosphorylation, cytokine independent growth characteristics. We conclude that the STAT5B N642H mutation is common in pediatric T-cell acute lymphoblastic leukemia and results in an activation of oncogenic pathways, conferring an increased risk of relapse.