Persistent Large Granular Lymphocyte Clonal Expansions: “The Root of Many Evils”—And of Some Goodness

SIMPLE SUMMARY: Large granular lymphocyte leukemia (LGLL) is a chronic disorder of either mature T or NK lymphocytes. As clonal expansions of the immune system cells, difficulties in the distinction between a true neoplasia and a physiological reactive process have been common since its description. We review here the different conditions associated with persistent clonal LGL expansions and discuss their potential origin and whether they can modulate the clinical features. ABSTRACT: Large granular lymphocyte leukemia (LGLL) is a chronic disease of either mature phenotype cytotoxic CD3+ T lymphocytes or CD3- NK cells. LGLL diagnosis is hampered by the fact that reactive persistent clonal LGL expansions may fulfill the current criteria for LGLL diagnoses. In addition to the presence of characteristic clinical and hematological signs such as anemia or neutropenia, LGLL/LGL clonal expansions have been associated with an array of conditions/disorders. We review here the presence of these persistent clonal expansions in autoimmune, hematological disorders and solid neoplasms and after hematopoietic stem cell transplantation. These associations are a unique translational research framework to discern whether these persistently expanded LGL clones are causes or consequences of the concomitant clinical settings and, more importantly, when they should be targeted.