Co-inhibition of NF-kappaB and JNK is synergistic in TNF-expressing human AML Journal Article

Authors: Volk, A; Li, J; Xin, J.; You, D.; Zhang, J; Liu, X; Xiao, Y.; Breslin, P; Li, Z; Wei, W.; Schmidt, R; Li, X; Zhang, Z; Kuo, P. C.; Nand, S; Chen, J
Article Title: Co-inhibition of NF-kappaB and JNK is synergistic in TNF-expressing human AML
Abstract: Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor kappaB (NF-kappaB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-kappaB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-kappaB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor alpha (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-kappaB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-kappaB inhibitor treatment by blocking the TNF-JNK-AP1 signaling pathway. Our data suggest that co-inhibition of both TNF-JNK-AP1 and NF-kappaB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC.
Journal Title: The Journal of experimental medicine
Volume: 211
Issue: 6
ISSN: 1540-9538; 0022-1007
Publisher: Volk et al  
Journal Place: United States
Date Published: 2014
Start Page: 1093
End Page: 1108
Language: eng
Notes: LR: 20150331; CI: (c) 2014; GR: F31CA174147-01/CA/NCI NIH HHS/United States; GR: P30 CA056036/CA/NCI NIH HHS/United States; GR: UL1 TR000430/TR/NCATS NIH HHS/United States; JID: 2985109R; 0 (Anthracenes); 0 (BAY 11-7085); 0 (NF-kappa B); 0 (Nitriles); 0 (Receptors, Tumor Necrosis Factor); 0 (Sulfones); 0 (TNF protein, human); 0 (Transcription Factor AP-1); 0 (Tumor Necrosis Factor-alpha); 0 (anthra(1,9-cd)pyrazol-6(2H)-one); EC (JNK Mitogen-Activated Protein Kinases); OID: NLM: PMC4042653; 2014/05/19 [aheadofprint]; ppublish