Subclonal STAT3 mutations solidify clonal dominance.

T large granular lymphocyte leukemia (T-LGLL) is a clonal lymphoproliferative disorder that can arise in the context of pathologic or physiologic cytotoxic T-cell (CTL) responses. STAT3 mutations are often absent in typical T-LGLL, suggesting that in a significant fraction of patients, antigen-driven expansion alone can maintain LGL clone persistence. We set out to determine the relationship between activating STAT3 hits and CTL clonal selection at presentation and in response to therapy. Thus, a group of patients with T-LGLL were serially subjected to deep next-generation sequencing (NGS) of the T-cell receptor (TCR) Vβ complementarity-determining region 3 (CDR3) and STAT3 to recapitulate clonal hierarchy and dynamics. The results of this complex analysis demonstrate that STAT3 mutations produce either a sweeping or linear subclone within a monoclonal CTL population either early or during the course of disease. Therapy can extinguish a LGL clone, silence it, or adapt mechanisms to escape elimination. LGL clones can persist on elimination of STAT3 subclones, and alternate STAT3-negative CTL clones can replace therapy-sensitive CTL clones. LGL clones can evolve and are fueled by a nonextinguished antigenic drive. STAT3 mutations can accelerate this process or render CTL clones semiautonomous and not reliant on physiologic stimulation.