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 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.
Molecular Biology Program, Department of Biology, Loyola University Chicago, Chicago, IL 60660.
Andrew
A
Volk
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai 200234, People's Republic of China.
Jing
J
Li
Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Junping
J
Xin
Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Dewen
D
You
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai 200234, People's Republic of China.
Jun
J
Zhang
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai 200234, People's Republic of China.
Xinli
X
Liu
Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Yechen
Y
Xiao
Molecular Biology Program, Department of Biology, Loyola University Chicago, Chicago, IL 60660 Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153 Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Peter
P
Breslin
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637.
Zejuan
Z
Li
Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Wei
W
Wei
Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Rachel
R
Schmidt
Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai 200234, People's Republic of China.
Xingyu
X
Li
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Zhou
Z
Zhang
Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Paul C
PC
Kuo
Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Sucha
S
Nand
Thomas Jefferson University, Jefferson Medical College, Department of Microbiology and Immunology, Philadelphia, PA 19107.
Jianke
J
Zhang
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637.
Jianjun
J
Chen
Molecular Biology Program, Department of Biology, Loyola University Chicago, Chicago, IL 60660 Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology; Department of Molecular and Cellular Physiology; and Department of Medicine, Loyola University Medical Center, Maywood, IL 60153 jzhang@lumc.edu.
Jiwang
J
Zhang
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D007948:Leukemia, Monocytic, Acute / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020298:U937 Cells
D000873:Anthracenes; C416282:BAY 11-7085; D016328:NF-kappa B; D009570:Nitriles; D018124:Receptors, Tumor Necrosis Factor; D013450:Sulfones; C439524:TNF protein, human; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases