Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor-treated CML stem cells.
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. We show here that CML LSC demonstrated increased expression of the IL-1 receptors, IL-1 receptor accessory protein and IL-1 receptor type 1 (IL-1R1), and enhanced sensitivity to IL-1-induced NF-κB signaling compared with 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.
Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA.
Bin
B
Zhang
Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL.
Su
S
Chu
Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL.
Puneet
P
Agarwal
College of Medical, Veterinary, & Life Sciences, Institute of Cancer Sciences, University of Glasgow, United Kingdom; and.
Victoria L
VL
Campbell
College of Medical, Veterinary, & Life Sciences, Institute of Cancer Sciences, University of Glasgow, United Kingdom; and.
Lisa
L
Hopcroft
College of Medical, Veterinary, & Life Sciences, Institute of Cancer Sciences, University of Glasgow, United Kingdom; and.
Heather G
HG
Jørgensen
Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA.
Allen
A
Lin
Department of Pathology, City of Hope National Medical Center, Duarte, CA.
Karl
K
Gaal
College of Medical, Veterinary, & Life Sciences, Institute of Cancer Sciences, University of Glasgow, United Kingdom; and.
Tessa L
TL
Holyoake
Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL.
Ravi
R
Bhatia
D000818:Animals; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
C508590:IL1R1 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D053573:Receptors, Interleukin-1 Type I