Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation.
Allan, Elaine K
Jørgensen, Heather G
Holyoake, Tessa L
American Society of Hematology
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Gallipoli, P., Pellicano, F., Morrison, H., Laidlaw, K., Allan, E. K., Bhatia, R., Copland, M., et al. (2013). Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation.. Blood, 122 (19), 3335-3339. https://doi.org/10.1182/blood-2013-02-485607
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.
Apoptosis, Cell Proliferation, Cell Survival, Chromones, Gene Expression Regulation, Leukemic, Humans, Indoles, Interleukin-3, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, NF-kappa B, Neoplastic Stem Cells, Primary Cell Culture, Protein Kinase Inhibitors, Pyrimidines, Receptors, Interleukin-3, Signal Transduction, Tumor Necrosis Factor-alpha
This study was supported by the Glasgow Experimental Cancer Medicine Centre , which is funded by Cancer Research UK and by the Chief Scientist’s Office, Scotland. Cell sorting facilities were funded by the Kay Kendall Leukaemia Fund (KKL501) and the Howat Foundation. Funding was provided by Medical Research Council UK clinical research training fellowship grant G1000288 (P.G.), Cancer Research UK Programme grant C11074/A11008 and the Elimination of Leukaemia Fund (ELF/6/ 29/1) (F.P.), National Institutes of Health, National Cancer Institute research grant R01 CA095684 (R.B.), by the Friends of Paul O’Gorman Leukaemia Research Centre (H.G.J.), and Cancer Research UK Programme grant C11074/A11008 (T.L.H.).
External DOI: https://doi.org/10.1182/blood-2013-02-485607
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266276