TY - JOUR
T1 - Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells
AU - Liang, Xueqing
AU - Moseman, E. Ashley
AU - Farrar, Michael A.
AU - Bachanova, Veronika
AU - Weisdorf, Daniel J.
AU - Blazar, Bruce R.
AU - Chen, Wei
PY - 2010/6/17
Y1 - 2010/6/17
N2 - 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 tetramethylrhodamine 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-κB-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.
AB - 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 tetramethylrhodamine 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-κB-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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U2 - 10.1182/blood-2009-03-213363
DO - 10.1182/blood-2009-03-213363
M3 - Article
C2 - 20339095
AN - SCOPUS:77954662424
SN - 0006-4971
VL - 115
SP - 5041
EP - 5052
JO - Blood
JF - Blood
IS - 24
ER -