Defining TCR gamma delta lymphoproliferative disorders by combined immunophenotypic and molecular evaluation

T gamma delta large granular lymphocyte leukemia (T gamma delta LGLL) is a rare lymphoproliferative neoplasm characterized by the expansion of T large granular lymphocytes expressing gamma delta TCR. Here, based on deep sequencing analysis of the clonotype repertoire, the authors show that leukemic T gamma delta cells are characterized by recurrent public clonotypes that are diversified between symptomatic and asymptomatic patients. T gamma delta large granular lymphocyte leukemia (T gamma delta LGLL) is a rare lymphoproliferative disease, scantily described in literature. A deep-analysis, in an initial cohort of 9 T gamma delta LGLL compared to 23 healthy controls, shows that T gamma delta LGLL dominant clonotypes are mainly public and exhibit different V-(D)-J gamma/delta usage between patients with symptomatic and indolent T gamma delta neoplasm. Moreover, some clonotypes share the same rearranged sequence. Data obtained in an enlarged cohort (n = 36) indicate the importance of a combined evaluation of immunophenotype and STAT mutational profile for the correct management of patients with T gamma delta cell expansions. In fact, we observe an association between V delta 2/V gamma 9 clonality and indolent course, while V delta 2/V gamma 9 negativity correlates with symptomatic disease. Moreover, the 7 patients with STAT3 mutations have neutropenia and a CD56-/V delta 2- phenotype, and the 3 cases with STAT5B mutations display an asymptomatic clinical course and CD56/V delta 2 expression. All these data indicate that biological characterization is needed for T gamma delta-cell neoplasm definition.