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 journalArticle

54 Citations (Scopus)

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

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Large Granular Lymphocytic Leukemia
Lymphocytes
Platelet-Derived Growth Factor
T-cells
Survival
Natural Killer Cells
Phosphatidylinositol 3-Kinase
T-Lymphocytes
Proto-Oncogene Proteins c-akt
Natural Killer T-Cells
src-Family Kinases
Platelets
Neutralizing Antibodies
Leukemia
Blood Platelets
Chemical activation
Switches
Apoptosis
Staining and Labeling
Plasmas

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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
Yang, Jun ; Liu, Xin ; Nyland, Susan B. ; Zhang, Ranran ; Ryland, Lindsay K. ; Broeg, Kathleen ; Baab, Kendall Thomas ; Jarbadan, Nancy Ruth ; Irby, Rosalyn ; Loughran, Thomas P. / Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway. In: Blood. 2010 ; Vol. 115, No. 1. pp. 51-60.
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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.",
author = "Jun Yang and Xin Liu and Nyland, {Susan B.} and Ranran Zhang and Ryland, {Lindsay K.} and Kathleen Broeg and Baab, {Kendall Thomas} and Jarbadan, {Nancy Ruth} and Rosalyn Irby and Loughran, {Thomas P.}",
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Yang, J, Liu, X, Nyland, SB, Zhang, R, Ryland, LK, Broeg, K, Baab, KT, Jarbadan, NR, Irby, R & Loughran, TP 2010, 'Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway', Blood, vol. 115, no. 1, pp. 51-60. https://doi.org/10.1182/blood-2009-06-223719

Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway. / Yang, Jun; Liu, Xin; Nyland, Susan B.; Zhang, Ranran; Ryland, Lindsay K.; Broeg, Kathleen; Baab, Kendall Thomas; Jarbadan, Nancy Ruth; Irby, Rosalyn; Loughran, Thomas P.

In: Blood, Vol. 115, No. 1, 07.01.2010, p. 51-60.

Research output: Contribution to journalArticle

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T1 - Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway

AU - Yang, Jun

AU - Liu, Xin

AU - Nyland, Susan B.

AU - Zhang, Ranran

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AU - Broeg, Kathleen

AU - Baab, Kendall Thomas

AU - Jarbadan, Nancy Ruth

AU - Irby, Rosalyn

AU - Loughran, Thomas P.

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N2 - 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.

AB - 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.

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