Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation

Gallipoli, P., Pellicano, F., Morrison, H., Laidlaw, K., Allan, E.K., Bhatia, R., Copland, M. , Jorgensen, H.G. and Holyoake, T.L. (2013) Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation. Blood, 122(19), pp. 3335-3339. (doi: 10.1182/blood-2013-02-485607) (PMID:24041577) (PMCID:PMC3953090)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gallipoli, Dr Paolo and Jorgensen, Dr Heather and Pellicano, Dr Francesca and Holyoake, Professor Tessa and Copland, Professor Mhairi and Morrison, Miss Heather and Allan, Mrs Elaine
Authors: Gallipoli, P., Pellicano, F., Morrison, H., Laidlaw, K., Allan, E.K., Bhatia, R., Copland, M., Jorgensen, H.G., and Holyoake, T.L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
540351The relevance of autocrine growth factor activation to the survival and proliferation of primitive chronic myeloid leukaemia (CML) cells.Paolo GallipoliMedical Research Council (MRC)G1000288RI CANCER SCIENCES
498551Key survival pathways in chronic myeloid leukaemic (CML) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES
597331An investigation of hsa-mir183 and E2F1 role in CML LSCFrancesca PellicanoELIMINATION OF LEUKAEMIA FUND (ELF-FUND)ELF/6/29/1ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C