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.
| Original language | English |
|---|---|
| Pages (from-to) | 3335-9 |
| Number of pages | 5 |
| Journal | Blood |
| Volume | 122 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 7 Nov 2013 |
Keywords
- Apoptosis
- Cell Proliferation
- Cell Survival
- Chromones
- Gene Expression Regulation, Leukemic
- Humans
- Indoles
- Interleukin-3
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- NF-kappa B
- Neoplastic Stem Cells
- Primary Cell Culture
- Protein Kinase Inhibitors
- Pyrimidines
- Receptors, Interleukin-3
- Signal Transduction
- Tumor Necrosis Factor-alpha
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't