title: Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets.
abstract: Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disorder of cytotoxic lymphocytes characterized by an expansion of CD3(+) cytotoxic T lymphocytes or CD3(-) natural killer cells. Patients present with various cytopenias including neutropenia, anemia and thrombocytopenia. In addition, there is an association of T-cell large granular lymphocytic leukemia with rheumatoid arthritis. It is believed that LGL leukemia begins as an antigen-driven immune response with subsequent constitutive activation of cytotoxic T lymphocytes or natural killer cells through PDGF and IL-15 contributing to their survival. Consequently, this leads to a dysregulation of apoptosis and dysfunction of the activation-induced cell death pathway. Treatment of LGL leukemia is based on a low-dose immunosuppressive regimen using methotrexate or cyclophosphamide. However, no standard of therapy has been established, as large prospective trials have not been conducted. In addition, some patients are refractory to treatment. The lack of a curative therapy for LGL leukemia means that new treatment options are needed. Insight into the various dysregulated signaling pathways in LGL leukemia may provide novel therapeutic treatment modalities.
authors: Penn State Hershey Cancer Institute, Experimental Therapeutics, Room 4427, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, USA.
authors: Francis
authors: F
authors: Leblanc
authors: Dan
authors: D
authors: Zhang
authors: Xin
authors: X
authors: Liu
authors: Thomas P
authors: TP
authors: Loughran
mesh_terms: D017209:Apoptosis / Q000276:immunology; D003520:Cyclophosphamide / Q000627:therapeutic use*; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D019409:Interleukin-15 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D054066:Leukemia, Large Granular Lymphocytic / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism*; D008727:Methotrexate / Q000627:therapeutic use*; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D016328:NF-kappa B; D013107:Sphingolipids; D003520:Cyclophosphamide; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins; D008727:Methotrexate