Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation (original) (raw)

Gallipoli, P., Pellicano, F., Morrison, H., Laidlaw, K., Allan, E.K., Bhatia, R., Copland, M. ORCID: https://orcid.org/0000-0002-7655-016X, Jorgensen, H.G. ORCID: https://orcid.org/0000-0003-4663-4191 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.

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Funder and Project Information

1

The relevance of autocrine growth factor activation to the survival and proliferation of primitive chronic myeloid leukaemia (CML) cells.

Paolo Gallipoli

G1000288

RI CANCER SCIENCES

Key survival pathways in chronic myeloid leukaemic (CML) stem cells and novel approaches to their eradication

Tessa Holyoake

C11074/A11008

SCS - Paul O'Gorman Leukaemia Research Centre

1

An investigation of hsa-mir183 and E2F1 role in CML LSC

Francesca Pellicano

ELF/6/29/1

ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C

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