Abstract
Chronic myeloid leukemia (CML) stem cells are not dependent on BCR-ABL kinase for their survival, suggesting that kinase-independent mechanisms must contribute to their persistence. We observed that CML stem/progenitor cells (SPCs) produce tumor necrosis factor-α (TNF-α) in a kinase-independent fashion and at higher levels relative to their normal counterparts. We therefore investigated the role of TNF-α and found that it supports survival of CML SPCs by promoting nuclear factor κB/p65 pathway activity and expression of the interleukin 3 and granulocyte/macrophage-colony stimulating factor common β-chain receptor. Furthermore, we demonstrate that in CML SPCs, inhibition of autocrine TNF-α signaling via a small-molecule TNF-α inhibitor induces apoptosis. Moreover TNF-α inhibition combined with nilotinib induces significantly more apoptosis relative to either treatment alone and a reduction in the absolute number of primitive quiescent CML stem cells. These results highlight a novel survival mechanism of CML SPCs and suggest a new putative therapeutic target for their eradication.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Chromones / pharmacology*
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Gene Expression Regulation, Leukemic
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Humans
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Indoles / pharmacology*
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Interleukin-3 / antagonists & inhibitors
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Interleukin-3 / genetics
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Interleukin-3 / immunology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / immunology
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Primary Cell Culture
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / pharmacology
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Receptors, Interleukin-3 / antagonists & inhibitors
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Receptors, Interleukin-3 / genetics
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Receptors, Interleukin-3 / immunology
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Signal Transduction
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
Substances
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Chromones
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Indoles
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Interleukin-3
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NF-kappa B
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Protein Kinase Inhibitors
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Pyrimidines
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Receptors, Interleukin-3
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Tumor Necrosis Factor-alpha
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nilotinib