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

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 inh...

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Autores principales: Volk, Andrew, Li, Jing, Xin, Junping, You, Dewen, Zhang, Jun, Liu, Xinli, Xiao, Yechen, Breslin, Peter, Li, Zejuan, Wei, Wei, Schmidt, Rachel, Li, Xingyu, Zhang, Zhou, Kuo, Paul C., Nand, Sucha, Zhang, Jianke, Chen, Jianjun, Zhang, Jiwang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042653/
https://www.ncbi.nlm.nih.gov/pubmed/24842373
http://dx.doi.org/10.1084/jem.20130990
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author Volk, Andrew
Li, Jing
Xin, Junping
You, Dewen
Zhang, Jun
Liu, Xinli
Xiao, Yechen
Breslin, Peter
Li, Zejuan
Wei, Wei
Schmidt, Rachel
Li, Xingyu
Zhang, Zhou
Kuo, Paul C.
Nand, Sucha
Zhang, Jianke
Chen, Jianjun
Zhang, Jiwang
author_facet Volk, Andrew
Li, Jing
Xin, Junping
You, Dewen
Zhang, Jun
Liu, Xinli
Xiao, Yechen
Breslin, Peter
Li, Zejuan
Wei, Wei
Schmidt, Rachel
Li, Xingyu
Zhang, Zhou
Kuo, Paul C.
Nand, Sucha
Zhang, Jianke
Chen, Jianjun
Zhang, Jiwang
author_sort Volk, Andrew
collection PubMed
description 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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spelling pubmed-40426532014-12-02 Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML Volk, Andrew Li, Jing Xin, Junping You, Dewen Zhang, Jun Liu, Xinli Xiao, Yechen Breslin, Peter Li, Zejuan Wei, Wei Schmidt, Rachel Li, Xingyu Zhang, Zhou Kuo, Paul C. Nand, Sucha Zhang, Jianke Chen, Jianjun Zhang, Jiwang J Exp Med Article 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. The Rockefeller University Press 2014-06-02 /pmc/articles/PMC4042653/ /pubmed/24842373 http://dx.doi.org/10.1084/jem.20130990 Text en © 2014 Volk et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Volk, Andrew
Li, Jing
Xin, Junping
You, Dewen
Zhang, Jun
Liu, Xinli
Xiao, Yechen
Breslin, Peter
Li, Zejuan
Wei, Wei
Schmidt, Rachel
Li, Xingyu
Zhang, Zhou
Kuo, Paul C.
Nand, Sucha
Zhang, Jianke
Chen, Jianjun
Zhang, Jiwang
Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
title Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
title_full Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
title_fullStr Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
title_full_unstemmed Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
title_short Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
title_sort co-inhibition of nf-κb and jnk is synergistic in tnf-expressing human aml
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042653/
https://www.ncbi.nlm.nih.gov/pubmed/24842373
http://dx.doi.org/10.1084/jem.20130990
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