title: Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation.
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.
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Scotland, United Kingdom;
authors.forename: Paolo
authors.initials: P
authors.lastname: Gallipoli
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellicano
authors.forename: Heather
authors.initials: H
authors.lastname: Morrison
authors.forename: Kamilla
authors.initials: K
authors.lastname: Laidlaw
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Allan
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.forename: Mhairi
authors.initials: M
authors.lastname: Copland
authors.forename: Heather G
authors.initials: HG
authors.lastname: Jørgensen
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007377:Interleukin-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016185:Receptors, Interleukin-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
chemical_list: D002867:Chromones; D007211:Indoles; D007377:Interleukin-3; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016185:Receptors, Interleukin-3; D014409:Tumor Necrosis Factor-alpha; C498826:nilotinib
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