High-frequency IL2RG-JAK1-JAK3-STAT5B mutations in T-PLL. (A-D) Representative IL2RG, JAK1, JAK3, and STAT5B mutations in primary T-PLL cells identified by WGS/WES and confirmed to be somatic by Sanger resequencing of tumor DNA (upper traces) and paired constitutional DNA (lower traces). (E) Schematic representations of mutations in IL2RG, JAK1, JAK3, and STAT5B identified through WGS, WES, or targeted Sanger resequencing of primary T-PLL (circles) and HUT78 cells (diamond). Confirmed somatic mutations are shown as filled symbols; variants where adequate matched constitutional DNA was not available are shown as open symbols. Mutations are clustered in the autoinhibitory pseudokinase domains of JAK1 and JAK3 (purple) or the SH2 domain of STAT5B (light blue) that mediates interactions between JAK and STAT proteins. One additional variant was detected in the kinase domain of JAK1 (red); a single case of T-PLL harbored a somatic 3-amino-acid deletion in the transmembrane domain of IL2RG (purple) as well as a somatic missense mutation in the cytoplasmic domain.