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)
Full text not currently available from Enlighten.
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: | Holyoake, Professor Tessa and Gallipoli, Dr Paolo and Jorgensen, Dr Heather and Copland, Professor Mhairi and Morrison, Miss Heather and Pellicano, Dr Francesca 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 > School 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 |
| Related URLs: |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information