Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis.
T-cell large granular lymphocytic leukemia (T-LGL) is characterized by chronic clonal lymphoproliferation of cytotoxic T lymphocytes (CTLs). Despite exhibiting phenotypic properties of antigen-activated cells, including expression of Fas and FasL, T-LGL cells accumulate and demonstrate resistance to apoptosis. We propose that increased activity of a prosurvival signaling pathway in T-LGL is responsible for attenuated apoptosis in T-LGL. Given the importance of the phosphatidylinositol-3 kinase (PI3K)-AKT pathway in regulating the balance between survival and apoptosis, we analyzed AKT activity in T-LGL cells. Compared with resting CTLs from healthy donors, patients' T-LGL cells showed higher levels of phosphorylated AKT. We demonstrate that phospho-AKT induction is dependent on the upstream activity of a Src family kinase. Since the PI3K-AKT pathway can antagonize the ability of Fas to initiate apoptosis, we hypothesized that inhibition of PI3K would lead to reacquisition of Fas sensitivity in T-LGL. Inhibition of the PI3K-AKT pathway alone led to brisk spontaneous apoptosis of T-LGL. These results suggest that T-LGL pathogenesis is dependent on activity of the PI3K-AKT pathway, without which the leukemic cells will begin to undergo spontaneous apoptosis. We propose that novel therapeutics inhibiting the PI3K-AKT axis may provide effective treatment for T-LGL.
Schade
Andrew E
AE
Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Powers
Jennifer J
JJ
Wlodarski
Marcin W
MW
Maciejewski
Jaroslaw P
JP
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051058:Oncogene Protein v-akt / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor / Q000276:immunology; D019061:src-Family Kinases / Q000276:immunology
D004791:Enzyme Inhibitors; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019014:fas Receptor; D019061:src-Family Kinases