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

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-alpha (TNF-alpha) in a kinase-independent fashion and at higher levels relative to their normal counterparts. We therefore investigated the role of TNF-alpha and found that it supports survival of CML SPCs by promoting nuclear factor kappa B/p65 pathway activity and expression of the interleukin 3 and granulocyte/macrophage-colony stimulating factor common beta-chain receptor. Furthermore, we demonstrate that in CML SPCs, inhibition of autocrine TNF-alpha signaling via a small-molecule TNF-alpha inhibitor induces apoptosis. Moreover TNF-alpha 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.