LGLL pathogenesis: polyclonal LGL expansion is thought to be initiated by a viral/autoantigen. LGL expansion is then sustained by inflammatory cytokines that can also contribute to the frequently associated autoimmune disorders. LGL expansion and clonal selection can also be favored by the occurrence of specific mutations including STAT3 and CCL22, inducing a resistance to apoptosis, increased proliferative capacities, and dysregulation of the cross talk with the immune microenvironment, respectively. Even in the absence of STAT3 mutation, the JAK-STAT pathway is activated in the majority of patients with LGLL. Epigenetic modifications have also been described with TET2 mutations, possibly representing an early event, observed in ∼30% of cases. Production of inflammatory cytokines and release of the cytotoxic granules by the leukemic LGLs in the infiltrated tissues lead to a spectrum of clinical and biological manifestations including cytopenia, fatigue, and autoimmune diseases. CCL22, C-C motif chemokine ligand 22; FasL: Fas ligand; IP10 (CXCL10), interferon-gamma–induced protein 10; PDGF, platelet-derived growth factor; STAT3, signal transducer and activator of transcription 3; TET2, ten-eleven translocation-2; TRAIL, tumor necrosis factor–related apoptosis-inducing ligand.