TY - JOUR
T1 - Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
AU - Volk, Andrew
AU - Li, Jing
AU - Xin, Junping
AU - You, Dewen
AU - Zhang, Jun
AU - Liu, Xinli
AU - Xiao, Yechen
AU - Breslin, Peter
AU - Li, Zejuan
AU - Wei, Wei
AU - Schmidt, Rachel
AU - Li, Xingyu
AU - Zhang, Zhou
AU - Kuo, Paul C.
AU - Nand, Sucha
AU - Zhang, Jianke
AU - Chen, Jianjun
AU - Zhang, Jiwang
PY - 2014/6
Y1 - 2014/6
N2 - Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK-AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF-JNK-AP1 signaling pathway. Our data suggest that co-inhibition of both TNF-JNK-AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC.
AB - Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK-AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF-JNK-AP1 signaling pathway. Our data suggest that co-inhibition of both TNF-JNK-AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC.
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U2 - 10.1084/jem.20130990
DO - 10.1084/jem.20130990
M3 - Article
C2 - 24842373
AN - SCOPUS:84901808678
SN - 0022-1007
VL - 211
SP - 1093
EP - 1108
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
ER -