Large granular lymphocyte (LGL) disorders account for several conditions characterized by the proliferation of clonal LGLs with cytotoxic activity. According to the LGL immunophenotype, most cases represent expansions of TCRα/β+ LGL, displaying a CD8+ CD4− or less frequently a CD4+ CD8−/+dim phenotype with variable expression of cytotoxic NK cell antigens, including CD57, CD16, and CD56. Clonal expansions of TCRγ/δ+ LGL are also described. Proliferations of CD3− CD16+ NK cells with a restricted pattern of NK receptors usually comprise 15% of the total. Morphologic, immunophenotypic and molecular analyses are mandatory for a correct diagnosis of disease. The JAK/STAT pathway is typically involved in sustaining LGL proliferation and recently the presence of STAT3 and STAT5B somatic mutations has been reported as a hallmark of the disease and included in the recent 2017 WHO classification. Understanding how the leukemic LGL clone survives is central to reconcile the molecular mechanisms to the clinical behavior of disease, in order to find new clues to overcome the still unacceptable limit of the conventional immunosuppressive treatments.
Large granular lymphocyte leukemia
Teramo A.;Vicenzetto C.;Barilà Gregorio;Calabretto G.;Gasparini V. R.;Semenzato G.;Zambello R.
2021
Abstract
Large granular lymphocyte (LGL) disorders account for several conditions characterized by the proliferation of clonal LGLs with cytotoxic activity. According to the LGL immunophenotype, most cases represent expansions of TCRα/β+ LGL, displaying a CD8+ CD4− or less frequently a CD4+ CD8−/+dim phenotype with variable expression of cytotoxic NK cell antigens, including CD57, CD16, and CD56. Clonal expansions of TCRγ/δ+ LGL are also described. Proliferations of CD3− CD16+ NK cells with a restricted pattern of NK receptors usually comprise 15% of the total. Morphologic, immunophenotypic and molecular analyses are mandatory for a correct diagnosis of disease. The JAK/STAT pathway is typically involved in sustaining LGL proliferation and recently the presence of STAT3 and STAT5B somatic mutations has been reported as a hallmark of the disease and included in the recent 2017 WHO classification. Understanding how the leukemic LGL clone survives is central to reconcile the molecular mechanisms to the clinical behavior of disease, in order to find new clues to overcome the still unacceptable limit of the conventional immunosuppressive treatments.
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