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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models

Author

  • Helena Ågerstam
  • Nils Hansen
  • Sofia von Palffy
  • Carl Sandén
  • Kristian Reckzeh
  • Christine Karlsson
  • Henrik Lilljebjörn
  • Niklas Landberg
  • Maria Askmyr
  • Carl Högberg
  • Marianne Rissler
  • Kimmo Porkka
  • Hans Wadenvik
  • Satu Mustjoki
  • Johan Richter
  • Marcus Järås
  • Thoas Fioretos
Show all

Summary, in English

Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD34(+)CD38(-)) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NF-κB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.

Department/s

  • Translational Genomic and Functional Studies of Leukemia
  • Division of Clinical Genetics
  • Stem Cell Center
  • Division of Molecular Medicine and Gene Therapy
  • Targeted therapies in leukemia
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy

Publishing year

2016-12-08

Language

English

Pages

2683-2693

Publication/Series

Blood

Volume

128

Issue

23

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Hematology

Status

Published

Research group

  • Translational Genomic and Functional Studies of Leukemia
  • Targeted therapies in leukemia

ISBN/ISSN/Other

  • ISSN: 1528-0020