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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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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. |
format | Online Article Text |
id | pubmed-4042653 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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