Abstract
Large granular lymphocyte (LGL) leukemia results from chronic expansion of cytotoxic T cells or natural killer (NK) cells. Apoptotic resistance resulting from constitutive activation of survival signaling pathways is a fundamental pathogenic mechanism. Recent network modeling analyses identified platelet-derived growth factor (PDGF) as a key master switch in controlling these survival pathways in T-cell LGL leukemia. Here we show that an autocrine PDGF regulatory loop mediates survival of leukemic LGLs of both T- and NK-cell origin. We found high levels of circulating PDGF-BB in platelet-poor plasma samples from LGL leukemia patients. Production of PDGF-BB by leukemic LGLs was demonstrated by immunocytochemical staining. Leukemic cells expressed much higher levels of PDGFR-beta transcripts than purified normal CD8(+) T cells or NK cells. We observed that phosphatidylinositol-3-kinase (PI3 kinase), Src family kinase (SFK), and downstream protein kinase B (PKB)/AKT pathways were constitutively activated in both T- and NK-LGL leukemia. Pharmacologic blockade of these pathways led to apoptosis of leukemic LGLs. Neutralizing antibody to PDGF-BB inhibited PKB/AKT phosphorylation induced by LGL leukemia sera. These results suggest that targeting of PDGF-BB, a pivotal regulator for the long-term survival of leukemic LGLs, may be an important therapeutic strategy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antibodies, Neutralizing / pharmacology
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Apoptosis / drug effects
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Autocrine Communication* / drug effects
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Becaplermin
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Enzyme-Linked Immunosorbent Assay
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Immunohistochemistry
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Leukemia, Large Granular Lymphocytic / blood
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Leukemia, Large Granular Lymphocytic / enzymology
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Leukemia, Large Granular Lymphocytic / genetics
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Leukemia, Large Granular Lymphocytic / pathology*
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Lymphocytes / drug effects
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Lymphocytes / enzymology
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Lymphocytes / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Platelet-Derived Growth Factor / genetics
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Platelet-Derived Growth Factor / metabolism*
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Platelet-Derived Growth Factor / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-sis
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Receptor, Platelet-Derived Growth Factor beta / genetics
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Signal Transduction* / drug effects
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Staining and Labeling
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src-Family Kinases / antagonists & inhibitors
Substances
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Antibodies, Neutralizing
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Phosphoinositide-3 Kinase Inhibitors
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Becaplermin
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Receptor, Platelet-Derived Growth Factor beta
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src-Family Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases