Current concepts: large granular lymphocyte leukemia

Clonal diseases of large granular lymphocyte(LGL) disorders can arise from a CD3+ T-cell lineage or from a CD3-NK-celllineage. CD3+ LGL leukemia is th e most frequent form of LGL leukemia. T-LGL leukemia usually affects elderl y people. Approximately 60% of patients are symptomatic; recurrent infectio ns secondary to chonic neutropenia, anemia, and rheumatoid arthrititis are the main clinical manifestations. The most common phenotype is CD3+, alpha beta+, CD8+, CD57+. Clonality is detected by clonal rearrangement of the T- cell receptor gene. NK-cell LGL proliferative disorders include NK LGL leuk emia which is a very aggressive disease and NK chronic lymphocytosis. Serol ogic findings show frequent reactivity to the BA21 epitope of HTLV-I env p2 1e, suggesting that a cellular or retroviral protein with homology to BA21 may be important in pathogenesis of these diseases. Clonal expansion may be facilitated by IL12 and IL15 cytokines expressed by leukemic LGL, and also by a defective Fas (CD95) apoptotic pathway. Leukemic LGL constitutively e xpress Fas and Fas-Ligand but they are resistant to Fas-induced apotosis. N eutropenia could be due to soluble Fas-Ligand which is highly secreted in t he patient's sera. Clinical and molecular remission can be obtained with or al low-dose methotrexate. Leukemic LGL express a multi-drug resistance phen otype (PgP+/LRP+) that could partly explain the chemoresistance observed in aggressive cases. It is suggested that LGL leukemia can serve as a useful model of dysregulated apoptosis as an underlying mechanism for both maligna ncy and autoimmune disease. (C) 1999 Harcourt Publishers Ltd.