Main deregulated pathways in LGLL: deregulation of apoptosis pathways is a key element in LGLL pathogenesis. LGL clones are resistant to the Fas-mediated apoptosis. Secreted soluble Fas (sFas) act as a decoy of FasL preventing the formation of the Fas-mediated death-inducing signaling complex (DISC). Apoptosis cascade is also inhibited by an increased level of an inhibitory protein named cellular FADD-like IL-1–converting enzyme inhibitory protein (c-FLIP). Ras and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways are also activated in LGLL and contribute to the apoptosis inhibition. The JAK-STAT pathway is constitutively activated in LGLL and leads to the transcription of B-cell lymphoma 2 (BCL-2) and myeloid cell leukemia 1 (Mcl-1) antiapoptotic proteins expression. Indeed, the JAK-STAT pathway is activated by several mechanisms. Gain-of-function STAT3 mutations are observed in 30% to 60% of patients and have recently been shown to trigger the expansion of cytotoxic LGL cells expressing high level of natural-killer group 2, member D (NKG2D). The JAK-STAT pathway is also activated downstream to the cytokines’ receptors. Increased secretion of inflammatory cytokines creates an autocrine loop. Mutations affecting genes implicated in epigenetic mechanisms such as ten-eleven translocation-2 (TET2) and lysine methyltransferase 2D (KMT2D) have been recently described. Gain-of-function CCL22 mutation induce a defect in its CCR4 receptor internalization, leading to an increase adhesion of myeloid and dendritic cells. These immune cells can stimulate LGL cells survival and proliferation in part by IL-15 secretion. Inflammatory cytokines secretion and cytotoxic granules release lead to the clinical symptoms and biological features observed in LGLL.