Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase

inhibitor treated CML stem cells (original) (raw)

Zhang, Bin, Chu, Su, Agarwal, Puneet, Campbell, Victoria L., Hopcroft, Lisa ORCID: https://orcid.org/0000-0002-7022-1322, Jørgensen, Heather G. ORCID: https://orcid.org/0000-0003-4663-4191, Lin, Allen, Gaal, Karl, Holyoake, Tessa L. and Bhatia, Ravi(2016) Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor treated CML stem cells.Blood, 128(23), pp. 2671-2682. (doi: 10.1182/blood-2015-11-679928) (PMID:27621307) (PMCID:PMC5146743)

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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 proinflammatory 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-KB 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.

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Funder and Project Information

1

Targeting p53, cMyc and PRC2 regulatory hubs: A systematic and stratified approach to deliver new therapeutics for CML

Tessa Holyoake

14033

ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C

Key survival pathways in chronic myeloid leukaemic (CML) stem cells and novel approaches to their eradication

Tessa Holyoake

C11074/A11008

SCS - Paul O'Gorman Leukaemia Research Centre

1

Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative studentship

Mhairi Copland

099710/Z/12/Z

ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C

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