title: Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway.
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.
authors.affiliation: Penn State Hershey Cancer Institute, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA. jyang@psu.edu
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Susan B
authors.initials: SB
authors.lastname: Nyland
authors.forename: Ranran
authors.initials: R
authors.lastname: Zhang
authors.forename: Lindsay K
authors.initials: LK
authors.lastname: Ryland
authors.forename: Kathleen
authors.initials: K
authors.lastname: Broeg
authors.forename: Kendall Thomas
authors.initials: KT
authors.lastname: Baab
authors.forename: Nancy Ruth
authors.initials: NR
authors.lastname: Jarbadan
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Irby
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects; D000077214:Becaplermin; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D054066:Leukemia, Large Granular Lymphocytic / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013194:Staining and Labeling; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D000077214:Becaplermin; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta; D019061:src-Family Kinases