title: Sensitizing leukemia stem cells to NF-κB inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling.
abstract: We previously reported that autocrine TNF-α (TNF) is responsible for JNK pathway activation in a subset of acute myeloid leukemia (AML) patient samples, providing a survival/proliferation signaling parallel to NF-κB in AML stem cells (LSCs). In this study, we report that most TNF-expressing AML cells (LCs) also express another pro-inflammatory cytokine, IL1β, which acts in a parallel manner. TNF was produced primarily by LSCs and leukemic progenitors (LPs), whereas IL1β was mainly produced by partially differentiated leukemic blasts (LBs). IL1β also stimulates an NF-κB-independent pro-survival and proliferation signal through activation of the JNK pathway. We determined that co-inhibition of signaling stimulated by both TNF and IL1β synergizes with NF-κB inhibition in eliminating LSCs both ex vivo and in vivo. Our studies show that such treatments are most effective in M4/5 subtypes of AML.
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, 200234, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Volk
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, 200234, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cannova
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, 200234, People's Republic of China.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Dai
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, 200234, People's Republic of China.
authors.forename: Caiqin
authors.initials: C
authors.lastname: Hao
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, 200234, People's Republic of China.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, 200234, People's Republic of China.
authors.forename: Jiewen
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, 200234, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.|Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA.|Department of Molecular and Cellular Physiology, Loyola University Medical Center, Maywood, IL 60153, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Breslin
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Sucha
authors.initials: S
authors.lastname: Nand
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.|Department of Pathology, Loyola University Medical Center, Maywood, IL. 60153, USA.
authors.forename: Ameet
authors.initials: A
authors.lastname: Kini
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.|Department of Pathology, Loyola University Medical Center, Maywood, IL. 60153, USA.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D000068800:Etanercept / Q000494:pharmacology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016328:NF-kappa B; D009570:Nitriles; D053573:Receptors, Interleukin-1 Type I; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013450:Sulfones; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
keywords: IL-1; JNK; NF-kappa B; TNF; leukemia stem cell