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Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor treated CML stem cells

Bin Zhang, Su Chu, Puneet Agarwal, Victoria L. Campbell, Lisa Hopcroft, Heather G. Jørgensen, Allen Lin, Karl Gaal, Tessa L. Holyoake and Ravi Bhatia

Key points

  • CML LSC demonstrate increased IL-1 receptor expression and enhanced signaling response.

  • Inhibition of IL-1 signaling using the antagonist IL-1RA enhances targeting of CML LSC in combination with TKI.

Abstract

Treatment of chronic myelogenous leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKI) fails to eliminate leukemia stem cells (LSC). Patients remain at risk for relapse, and additional approaches to deplete CML LSC are needed to enhance the possibility of discontinuing TKI treatment. We have previously reported that expression of the pivotal pro-inflammatory cytokine interleukin-1 (IL-1) is increased in CML bone marrow (BM). We show here that CML LSC demonstrated increased expression of the IL-1 receptors, IL-1RAP and IL-1R1, and enhanced sensitivity to IL-1-induced NF-κB signaling compared to normal stem cells. Treatment with recombinant IL-1 receptor antagonist (IL-1RA) inhibited IL-1 signaling in CML LSC and inhibited growth of CML LSC. Importantly, the combination of IL-1RA with TKI resulted in significantly greater inhibition of CML LSC compared with TKI alone. Our studies also suggest that IL-1 signaling contributes to overexpression of inflammatory mediators in CML LSC, suggesting that blocking IL-1 signaling could modulate the inflammatory milieu. We conclude that IL-1 signaling contributes to maintenance of CML LSC following TKI treatment, and that IL-1 blockade with IL-1RA enhances elimination of TKI-treated CML LSC. These results provide a strong rationale for further exploration of anti-IL-1 strategies to enhance LSC elimination in CML.

  • Submitted November 5, 2015.
  • Accepted August 24, 2016.