High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

Recurrent gain-of-function mutations in the transcription factors STAT5A and much more in STAT5B were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms (peripheral T-cell lymphoma). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for peripheral T-cell lymphoma, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive Stat5a or STAT5B variants at low or high levels in the hematopoietic system of transgenic mice. Only high activity levels developed a lethal disease resembling human peripheral T-cell lymphoma. Neoplasia displayed massive expansion of CD8 + T-cells and destructive organ-infiltration. T-cells were cytokine-hypersensitive with activated memory CD8+ T-lymphocyte characteristics. Histopathology analysis and mRNA expression profiles revealed close correlation with distinct human peripheral T-cell lymphoma subtypes. Pronounced STAT5 expression and activity in patient samples of different subsets underlines the relevance of JAK/STAT as therapeutic target. JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death and Ruxolitinib blocked T-cell neoplasia in vivo. We conclude that enhanced STAT5A or STAT5B action both drive peripheral T-cell lymphoma development, defining both STAT5 molecules as targets for therapeutic intervention.