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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2010-1-8
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.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-10508235, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-10746662, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-11160159, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-11846609, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-11912193, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-12750175, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-12876667, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-12972194, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-14726391, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-15230868, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-15516985, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-16078232, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-16484592, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-16530387, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-1660523, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-17172839, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-17596907, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-17893914, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-17993614, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-18477771, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-1851574, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-18768393, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-18852469, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-1969656, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-2156959, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-2160260, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-2838779, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-2846698, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-7685273, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-8599969, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-8983084, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-9292532, http://linkedlifedata.com/resource/pubmed/commentcorrection/19880494-9609528
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1528-0020
pubmed:author
pubmed:issnType
Electronic
pubmed:day
7
pubmed:volume
115
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
51-60
pubmed:dateRevised
2011-7-20
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
pubmed:year
2010
pubmed:articleTitle
Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway.
pubmed:affiliation
Penn State Hershey Cancer Institute, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA. jyang@psu.edu
pubmed:publicationType
Journal Article
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