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: Jing Li, Andrew Volk, Jun Zhang, Joseph Cannova, Shaojun Dai, Caiqin Hao, Chenglong Hu, Jiewen Sun, Yan Xu, Wei Wei, Peter Breslin, Sucha Nand, Jianjun Chen, Ameet Kini, Jiang Zhu, Jiwang Zhang
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 5 Pg. 8420-8435 (Jan 31 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28039479 (Publication Type: Journal Article)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• IL1B protein, mouse
• IL1R1 protein, mouse
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1beta
• NF-kappa B
• Nitriles
• Receptors, Interleukin-1 Type I
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Sulfones
• Tnfrsf1a protein, mouse
• Tumor Necrosis Factor-alpha
• Etanercept

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Etanercept (pharmacology)
• Humans
• Interleukin 1 Receptor Antagonist Protein (pharmacology)
• Interleukin-1beta (antagonists & inhibitors, metabolism)
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Nitriles (pharmacology)
• Receptors, Interleukin-1 Type I (genetics, metabolism)
• Receptors, Tumor Necrosis Factor, Type I (deficiency, genetics)
• Receptors, Tumor Necrosis Factor, Type II (deficiency, genetics)
• Signal Transduction (drug effects)
• Sulfones (pharmacology)
• Time Factors
• Transfection
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)