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

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

Research output: Contribution to journalArticlepeer-review

54 Citations (SciVal)

Abstract

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.

Original languageEnglish
Pages (from-to)2683-2693
JournalBlood
Volume128
Issue number23
DOIs
Publication statusPublished - 2016 Dec 8

Subject classification (UKÄ)

  • Hematology

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