Sensitizing leukemia stem cells to NF-κB inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling
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Jing Li1,*, Andrew Volk2,*, Jun Zhang1, Joseph Cannova2, Shaojun Dai1, Caiqin Hao1, Chenglong Hu1, Jiewen Sun1, Yan Xu1, Wei Wei2, Peter Breslin2,3,4, Sucha Nand2, Jianjun Chen5, Ameet Kini2,6, Jiang Zhu7, Jiwang Zhang2,6
1Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, 200234, People’s Republic of China
2Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA
3Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA
4Department of Molecular and Cellular Physiology, Loyola University Medical Center, Maywood, IL 60153, USA
5Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA
6Department of Pathology, Loyola University Medical Center, Maywood, IL. 60153, USA
7State 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
*These authors have contributed equally to this work
Jiwang Zhang: email: [email protected]
Keywords: leukemia stem cell, NF-kappa B, IL-1, TNF, JNK
Received: September 22, 2016 Accepted: November 23, 2016 Published: December 26, 2016
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.
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