rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2010-1-8
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-10508235,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-10746662,
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1528-0020
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
7
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pubmed:volume |
115
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
51-60
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pubmed:dateRevised |
2011-7-20
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pubmed:meshHeading |
pubmed-meshheading:19880494-Antibodies, Neutralizing,
pubmed-meshheading:19880494-Apoptosis,
pubmed-meshheading:19880494-Autocrine Communication,
pubmed-meshheading:19880494-Cell Line, Tumor,
pubmed-meshheading:19880494-Cell Proliferation,
pubmed-meshheading:19880494-Cell Survival,
pubmed-meshheading:19880494-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:19880494-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:19880494-Gene Expression Regulation, Leukemic,
pubmed-meshheading:19880494-Humans,
pubmed-meshheading:19880494-Immunohistochemistry,
pubmed-meshheading:19880494-Leukemia, Large Granular Lymphocytic,
pubmed-meshheading:19880494-Lymphocytes,
pubmed-meshheading:19880494-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:19880494-Phosphorylation,
pubmed-meshheading:19880494-Platelet-Derived Growth Factor,
pubmed-meshheading:19880494-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:19880494-Receptor, Platelet-Derived Growth Factor beta,
pubmed-meshheading:19880494-Signal Transduction,
pubmed-meshheading:19880494-Staining and Labeling,
pubmed-meshheading:19880494-src-Family Kinases
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pubmed:year |
2010
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pubmed:articleTitle |
Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway.
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pubmed:affiliation |
Penn State Hershey Cancer Institute, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA. jyang@psu.edu
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pubmed:publicationType |
Journal Article
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