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IL1RAP antibodies block IL1-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 and Thoas Fioretos

Key points

  • IL1 activates signaling and promotes proliferation of primitive CML cells.

  • IL1RAP antibodies block IL1-induced effects and mediate cell killing in chronic and blast phase CML in vivo models.

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. IL1RAP (IL1R3) is a co-receptor of IL1R1 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 IL1 receptor complex and respond with NFKB activation and marked proliferation in response to IL1. IL1RAP antibodies that inhibit IL1 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 rational for the development of an IL1RAP antibody therapy to target residual CML stem cells.

  • Submitted November 4, 2015.
  • Accepted September 2, 2016.