Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway

Jun Yang, Xin Liu, Susan B. Nyland, Ranran Zhang, Lindsay K. Ryland, Kathleen Broeg, Kendall Thomas Baab, Nancy Ruth Jarbadan, Rosalyn Irby, Thomas P. Loughran

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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-β 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 NKLGL leukemia. Pharmacologic blockade of these pathways led to apoptosis of leukemic LGLs. Neutralizing antibody toPDGF-BB inhibitedPKB/AKTphosphorylation 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.

Original languageEnglish (US)
Pages (from-to)51-60
Number of pages10
JournalBlood
Volume115
Issue number1
DOIs
StatePublished - Jan 7 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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