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

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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. © 2010 by The American Society of Hematology.

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Yang, J., Liu, X., Nyland, S. B., Zhang, R., Ryland, L. K., Broeg, K., … Loughran, T. P. (2010). Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway. Blood, 115(1), 51–60. https://doi.org/10.1182/blood-2009-06-223719

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