Sensitizing leukemia stem cells to NF-kappaB inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling Journal Article

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Authors: Li, J; Volk, A; Zhang, J; Cannova, J.; Dai, S.; Hao, C.; Hu, C; Sun, J; Xu, Y; Wei, W.; Breslin, P; Nand, S; Chen, J; Kini, A; Zhu, J.
Article Title: Sensitizing leukemia stem cells to NF-kappaB inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling
Abstract: We previously reported that autocrine TNF-alpha (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-kappaB in AML stem cells (LSCs). In this study, we report that most TNF-expressing AML cells (LCs) also express another pro-inflammatory cytokine, IL1beta, which acts in a parallel manner. TNF was produced primarily by LSCs and leukemic progenitors (LPs), whereas IL1beta was mainly produced by partially differentiated leukemic blasts (LBs). IL1beta also stimulates an NF-kappaB-independent pro-survival and proliferation signal through activation of the JNK pathway. We determined that co-inhibition of signaling stimulated by both TNF and IL1beta synergizes with NF-kappaB 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.
Journal Title: Oncotarget
Volume: 8
Issue: 5
ISSN: 1949-2553; 1949-2553
Publisher: Unknown  
Journal Place: United States
Date Published: 2017
Start Page: 8420
End Page: 8435
Language: eng
DOI/URL:

10.18632/oncotarget.14220
Notes: LR: 20170416; JID: 101532965; OTO: NOTNLM; 2016/09/22 [received]; 2016/11/23 [accepted]; ppublish