PMID- 24842373
OWN - NLM
STAT- MEDLINE
DCOM- 20140820
LR  - 20220408
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 211
IP  - 6
DP  - 2014 Jun 2
TI  - Co-inhibition of NF-kappaB and JNK is synergistic in TNF-expressing human AML.
PG  - 1093-108
LID - 10.1084/jem.20130990 [doi]
AB  - Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients 
      are more sensitive to nuclear factor kappaB (NF-kappaB) inhibition-induced cell death 
      when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro 
      culture. However, inadequate anti-leukemic activity of NF-kappaB inhibition in vivo 
      suggests the presence of additional survival/proliferative signals that can 
      compensate for NF-kappaB inhibition. AML subtypes M3, M4, and M5 cells produce 
      endogenous tumor necrosis factor alpha (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-kappaB, 
      leading to the up-regulation of anti-apoptotic genes in LC. We found that we can 
      significantly sensitize LC to NF-kappaB inhibitor treatment by blocking the 
      TNF-JNK-AP1 signaling pathway. Our data suggest that co-inhibition of both 
      TNF-JNK-AP1 and NF-kappaB signals may provide a more comprehensive treatment paradigm 
      for AML patients with TNF-expressing LC.
CI  - (c) 2014 Volk et al.
FAU - Volk, Andrew
AU  - Volk A
AD  - Molecular Biology Program, Department of Biology, Loyola University Chicago, 
      Chicago, IL 60660.
FAU - Li, Jing
AU  - Li J
AD  - Department of Biology, College of Life and Environment Science, Shanghai Normal 
      University, Shanghai 200234, People's Republic of China.
FAU - Xin, Junping
AU  - Xin J
AD  - 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.
FAU - You, Dewen
AU  - You D
AD  - 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.
FAU - Zhang, Jun
AU  - Zhang J
AD  - Department of Biology, College of Life and Environment Science, Shanghai Normal 
      University, Shanghai 200234, People's Republic of China.
FAU - Liu, Xinli
AU  - Liu X
AD  - Department of Biology, College of Life and Environment Science, Shanghai Normal 
      University, Shanghai 200234, People's Republic of China.
FAU - Xiao, Yechen
AU  - Xiao Y
AD  - 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.
FAU - Breslin, Peter
AU  - Breslin P
AD  - 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.
FAU - Li, Zejuan
AU  - Li Z
AD  - Section of Hematology/Oncology, Department of Medicine, University of Chicago, 
      Chicago, IL 60637.
FAU - Wei, Wei
AU  - Wei W
AD  - 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.
FAU - Schmidt, Rachel
AU  - Schmidt R
AD  - 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.
FAU - Li, Xingyu
AU  - Li X
AD  - Department of Biology, College of Life and Environment Science, Shanghai Normal 
      University, Shanghai 200234, People's Republic of China.
FAU - Zhang, Zhou
AU  - Zhang Z
AD  - Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, 
      People's Republic of China.
FAU - Kuo, Paul C
AU  - Kuo PC
AD  - 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.
FAU - Nand, Sucha
AU  - Nand S
AD  - 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.
FAU - Zhang, Jianke
AU  - Zhang J
AD  - Thomas Jefferson University, Jefferson Medical College, Department of 
      Microbiology and Immunology, Philadelphia, PA 19107.
FAU - Chen, Jianjun
AU  - Chen J
AD  - Section of Hematology/Oncology, Department of Medicine, University of Chicago, 
      Chicago, IL 60637.
FAU - Zhang, Jiwang
AU  - Zhang J
AD  - 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.
LA  - eng
GR  - F31 CA174147/CA/NCI NIH HHS/United States
GR  - P30 CA056036/CA/NCI NIH HHS/United States
GR  - UL1 TR000430/TR/NCATS NIH HHS/United States
GR  - F31CA174147-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140519
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Anthracenes)
RN  - 0 (BAY 11-7085)
RN  - 0 (NF-kappa B)
RN  - 0 (Nitriles)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Sulfones)
RN  - 0 (TNF protein, human)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 1TW30Y2766 (pyrazolanthrone)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Anthracenes/pharmacology
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects/genetics
MH  - Cells, Cultured
MH  - Gene Expression Regulation, Leukemic/drug effects
MH  - HL-60 Cells
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/antagonists & 
      inhibitors/genetics/*metabolism
MH  - K562 Cells
MH  - Leukemia, Monocytic, Acute/genetics/metabolism
MH  - Leukemia, Myeloid, Acute/genetics/*metabolism/pathology
MH  - Leukemia, Myelomonocytic, Acute/genetics/metabolism
MH  - Leukemia, Promyelocytic, Acute/genetics/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - NF-kappa B/antagonists & inhibitors/genetics/*metabolism
MH  - Nitriles/pharmacology
MH  - Receptors, Tumor Necrosis Factor/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/drug effects/genetics
MH  - Sulfones/pharmacology
MH  - Transcription Factor AP-1/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism/pharmacology
MH  - U937 Cells
PMC - PMC4042653
EDAT- 2014/05/21 06:00
MHDA- 2014/08/21 06:00
PMCR- 2014/12/02
CRDT- 2014/05/21 06:00
PHST- 2014/05/21 06:00 [entrez]
PHST- 2014/05/21 06:00 [pubmed]
PHST- 2014/08/21 06:00 [medline]
PHST- 2014/12/02 00:00 [pmc-release]
AID - jem.20130990 [pii]
AID - 20130990 [pii]
AID - 10.1084/jem.20130990 [doi]
PST - ppublish
SO  - J Exp Med. 2014 Jun 2;211(6):1093-108. doi: 10.1084/jem.20130990. Epub 2014 May 
      19.