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.
Breslin, Peter W.; Li, Jing; Volk, Andrew; Zhang, Jun; Cannova, Joseph; Dai, Shaojun; Hao, Caiqin; Hu, Chenglong; Sun, Jiewen; Xu, Yan; Wei, Wei; nand, Sucha; Chen, Jianjun; Kini, Ameet; Zhu, Jiang; and Zhang, Jiwang. Sensitizing Leukemia Stem Cells to NF-κB Inhibitor Treatment in Vivo by Inactivation of Both TNF and IL-1 Signaling. Oncotarget, 8, : 8420-8435, 2017. Retrieved from Loyola eCommons, Biology: Faculty Publications and Other Works, http://dx.doi.org/10.18632/oncotarget.14220
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