John Libbey Eurotext

Hématologie

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Spectrum of large granular lymphocyte leukemia and new pathogenetic features Volume 5, issue 4, Juillet - Août 1999

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Clonal diseases of large granular lymphocyte (LGL) disorders can arise from a CD3+ T-cell lineage or from a CD3– NK-cell lineage. CD3+ LGL leukemia is the most frequent form of LGL leukemia. T-LGL leukemia affects elderly people. Approximately 60% of patients are symptomatic; recurrent infections secondary to chronic neutropenia, anemia, and rheumatoid arthritis are the main clinical manifestations. The most common phenotype is CD3+, alphabeta+, CD8+, CD57+. Clonality is detected by clonal rearrangement of the T-cell receptor gene. NK-cell LGL proliferative disorders include NK LGL leukemia which is a very aggressive disease and NK chronic lymphocytosis. Serologic findings show frequent reactivity to the BA21 epitope of HTLV-I env p21e, 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 IL-12 and IL-15 cytokines expressed by leukemic LGL, and also by a defective Fas (CD95) apoptotic pathway. Leukemic LGL constitutively express Fas and Fas-Ligand but they are resistant to Fas-induced apoptosis. Neutropenia could be due to soluble Fas-Ligand which is highly secreted in the patient’s sera. Clinical and molecular remission can be obtained with oral low-dose methotrexate. Leukemic LGL express a multi-drug resistance phenotype (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 malignancy and autoimmune disease.