LAUSR

Large granular lymphocyte leukemia (LGLL) is a rare clonal disease characterized by an excess of CD8+ cytotoxic T cells or natural killer (NK) cells and associated with severe cytopenias, recurrent infections, and autoimmune diseases. Known LGLL hallmarks are JAK/STAT pathway activation, deregulation of proapoptotic pathways (sphingolipid and FAS/FAS ligand), and activation of pro-survival signaling pathways (PI3K/ AKT and RAS). Aberrant STAT signaling is observed in LGLL due to somatic mutations or to other mechanisms, such as epigenetic inactivation of JAK-STAT pathway inhibitors and increased interleukin-6 secretion. Activating STAT3 somatic mutations are frequently (30-70%) present in the SH2-domain [1] and very rarely (2%) in the DNAbinding or coiled-coil domain [2]. STAT5B mutations are more rare, but typical of CD4+ T-LGLL (50%) [3]. In a recent study [4] consisting of 19 LGLL patients, we characterized the genomic landscape of somatic mutations in LGLL including STAT-mutation negative cases. Altogether, 347 different genes carrying high confidence rare somatic variants with a strong functional impact were discovered. In addition to genes recurrently mutated, novel genes emerged from functional prioritization by a system genetics approach. Different LGLL patient subgroups, albeit showing similar clinical characteristics, had different mutation profiles with significantly higher mutation burden in CD4+ T-LGLL, possibly in relation to cytomegalovirus-derived stimulation and restricted usage of TCR Vβ. In addition to mutations of STAT3 in CD8+, and of STAT5B both in CD4+ and in CD8+ cases, 14 genes were recurrently mutated, including transcriptional/epigenetic regulator, tumor suppressor and cell proliferation genes. Of them, both KMT2D histone methyltransferase, and PCLO calcium sensor regulating cAMP-induced exocytosis were previously linked to lymphomagenesis. Two genes, ARL13B and FAT4, recurrently mutated in a mutually exclusive way were involved in control of cell growth Editorial