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Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells.

Publication ,  Journal Article
Liang, X; Moseman, EA; Farrar, MA; Bachanova, V; Weisdorf, DJ; Blazar, BR; Chen, W
Published in: Blood
June 17, 2010

Chronic lymphocytic leukemia (CLL) is the most prevalent human leukemia and is characterized by the progressive accumulation of long-lived malignant B cells. Here we show that human B-CLL cells selectively express high levels of Toll-like receptor 9 (TLR9) mRNA and proteins. Treating B-CLL cells with TLR9 agonists, type B CpG oligodeoxynucleotides (CpG-B ODNs), induces significant morphologic and phenotypic activation, altered cytokine production, reversal of signal transducer, and activator of transcription 1 (STAT1) phosphorylation state, followed by profound apoptosis of B-CLL cells that is CpG-B ODN treatment time- and dose-dependent. TLR9-CpG ODN ligation-induced apoptosis of B-CLL cells is confirmed by viable cell counts, annexin V/propidium iodide and tetramethyl-rhodamine ethylester staining, Western blots of the activation, and cleaved caspases and poly (ADP-ribose) polymerase. Triggering TLR9 by CpG-B ODN leads to nuclear factor-kappaB-dependent production of autocrine interleukin-10, which activates JAK/STAT pathway-dependent tyrosine phosphorylation of STAT1 proteins and thereby provokes an apoptosis pathway in B-CLL cells. Treating B-CLL cells in vitro or in vivo with CpG-B ODN reduces the number of leukemia cells that engraft in NOD-scid mice. These findings provide new understanding of CpG ODN-mediated antitumor effects and support for the development of TLR9-targeted therapy for human CLL.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

June 17, 2010

Volume

115

Issue

24

Start / End Page

5041 / 5052

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Toll-Like Receptor 9
  • Signal Transduction
  • STAT1 Transcription Factor
  • Receptors, Interleukin-2
  • Oligodeoxyribonucleotides
  • NF-kappa B
  • Middle Aged
  • Mice, SCID
 

Citation

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Liang, X., Moseman, E. A., Farrar, M. A., Bachanova, V., Weisdorf, D. J., Blazar, B. R., & Chen, W. (2010). Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells. Blood, 115(24), 5041–5052. https://doi.org/10.1182/blood-2009-03-213363
Liang, Xueqing, E Ashley Moseman, Michael A. Farrar, Veronika Bachanova, Daniel J. Weisdorf, Bruce R. Blazar, and Wei Chen. “Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells.Blood 115, no. 24 (June 17, 2010): 5041–52. https://doi.org/10.1182/blood-2009-03-213363.
Liang X, Moseman EA, Farrar MA, Bachanova V, Weisdorf DJ, Blazar BR, et al. Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells. Blood. 2010 Jun 17;115(24):5041–52.
Liang, Xueqing, et al. “Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells.Blood, vol. 115, no. 24, June 2010, pp. 5041–52. Pubmed, doi:10.1182/blood-2009-03-213363.
Liang X, Moseman EA, Farrar MA, Bachanova V, Weisdorf DJ, Blazar BR, Chen W. Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells. Blood. 2010 Jun 17;115(24):5041–5052.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

June 17, 2010

Volume

115

Issue

24

Start / End Page

5041 / 5052

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Toll-Like Receptor 9
  • Signal Transduction
  • STAT1 Transcription Factor
  • Receptors, Interleukin-2
  • Oligodeoxyribonucleotides
  • NF-kappa B
  • Middle Aged
  • Mice, SCID