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

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

SUBMITTER: Gallipoli P 

PROVIDER: S-EPMC3953090 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other