Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
| Autor: | Andrew Volk, Peter Breslin, Yechen Xiao, Wei Wei, Jianke Zhang, Zhou Zhang, Jianjun Chen, Dewen You, Xingyu Li, Xinli Liu, Rachel Schmidt, Jun Zhang, Jiwang Zhang, Paul C. Kuo, Junping Xin, Jing Li, Sucha Nand, Zejuan Li |
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| Rok vydání: | 2014 |
| Předmět: |
Programmed cell death
Myeloid Cell Survival Necroptosis Blotting Western Immunology HL-60 Cells Biology Article Leukemia Myelomonocytic Acute Receptors Tumor Necrosis Factor Mice Leukemia Promyelocytic Acute Cell Line Tumor Nitriles medicine Animals Humans Immunology and Allergy Sulfones Progenitor cell Cells Cultured Anthracenes Mice Knockout Gene Expression Regulation Leukemic Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha JNK Mitogen-Activated Protein Kinases NF-kappa B U937 Cells 3. Good health Transcription Factor AP-1 Leukemia Myeloid Acute Haematopoiesis medicine.anatomical_structure Leukemia Monocytic Acute Cancer research Tumor necrosis factor alpha Stem cell K562 Cells Signal Transduction K562 cells |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20130990 |
| Popis: | TNF signaling inactivation sensitizes AML cells to NF-kB inhibition but protects healthy hematopoietic stem progenitor cells from this treatment. 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. |
| Databáze: | OpenAIRE |
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