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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., Jørgensen, H.G., Holyoake, T.L.

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.

Citation

Gallipoli, P., Pellicano, F., Morrison, H., Laidlaw, K., Allan, E.K., Bhatia, R., Copland, M., Jørgensen, H.G., Holyoake, T.L. "Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation" Blood (2013): 3,335–9