The current status of relationships between STAT mutations and clinical features according to recently published studies.^3,5,6,8 Y640F and D661Y are the most frequent STAT3 genetic lesions. For the STAT5b gene, the most common mutations are N642H and Y665F, which are largely found in the SH2 domain. Other less frequent point mutations and insertion or deletions have been found, including the hotspot PIK3R1 mutations and the recurrent mutations in the death domain of FAS, as reported by Cheon et al. The resulting constitutive activation of STAT3 and STAT5b genes translates both into global hypermethylation and into the upregulation of expression of genes that are required for cytokine signaling, cell proliferation, and survival, such as c-Myc, cyclins D1 and D2, Bcl-xl, and Mcl1. Despite the high incidence of STAT genetic lesions, other recurrently mutated genes have been found, including TNFAIP3 and, less frequently, BCL11B, FLT3, and PTPN23 in T-LGLL. Professional illustration by Somersault18:24.