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

Research output: Contribution to journalArticle

Published copy (DOI)

Author(s)

  • Paolo Gallipoli
  • Francesca Pellicano
  • Heather Morrison
  • Kamilla Laidlaw
  • Elaine K Allan
  • Ravi Bhatia
  • Mhairi Copland
  • Heather G Jørgensen
  • Tessa L Holyoake

Department/unit(s)

Publication details

JournalBlood
DatePublished - 7 Nov 2013
Issue number19
Volume122
Number of pages5
Pages (from-to)3335-9
Original languageEnglish

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.

    Research areas

  • 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

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