Model of LGL leukemia pathogenesis. Activation and expansion occur, resulting in an oligoclonal cytotoxic lymphocyte population (colored outline represents a distinct clone, blue triangle represents an unknown antigen). STAT3 is activated and may acquire a mutation. Chronic antigen stimulation leads to expansion of one dominant (monoclonal) cytotoxic lymphocyte population (all are outlined in black signifying the monoclonal population). Three outcomes occur. In panel 1, the production of inflammatory cytokines (starburst shapes representing: IFN-γ, IL-8, IL-10, IL-1β, IL-12p35, IL-18, IL-1Ra, RANTES, MIP1-α, and MIP1-β) causes symptoms such as neutropenia, anemia, and fatigue, and can also cause an autoimmune disease such as RA. In panel 2, the functional killer cells release cytotoxic granules containing perforin and granzyme B (purple dots); this leads to the same outcomes as in panel 1. In panel 3, the STAT3-mediated survival network results in a persisting clone due to profound dysregulation of apoptosis, including resistance to Fas/FasL-mediated death and upregulation of Mcl-1. IFN, interferon; MIP, macrophage inflammatory protein.