Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML

Andrew Volk, Jing Li, Junping Xin, Dewen You, Jun Zhang, Xinli Liu, Yechen Xiao, Peter Breslin, Zejuan Li, Wei Wei, Rachel Schmidt, Xingyu Li, Zhou Zhang, Paul C. Kuo, Sucha Nand, Jianke Zhang, Jianjun Chen, Jiwang Zhang

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1093-1108
Number of pages16
JournalJournal of Experimental Medicine
Volume211
Issue number6
DOIs
StatePublished - Jun 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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