IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models.
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 of Clinical Genetics, Lund University, Lund, Sweden.
Helena
H
Ågerstam
Department of Clinical Genetics, Lund University, Lund, Sweden.
Nils
N
Hansen
Department of Clinical Genetics, Lund University, Lund, Sweden.
Sofia
S
von Palffy
Department of Clinical Genetics, Lund University, Lund, Sweden.
Carl
C
Sandén
Department of Clinical Genetics, Lund University, Lund, Sweden.
Kristian
K
Reckzeh
Department of Clinical Genetics, Lund University, Lund, Sweden.
Christine
C
Karlsson
Department of Clinical Genetics, Lund University, Lund, Sweden.
Henrik
H
Lilljebjörn
Department of Clinical Genetics, Lund University, Lund, Sweden.
Niklas
N
Landberg
Department of Clinical Genetics, Lund University, Lund, Sweden.
Maria
M
Askmyr
Department of Clinical Genetics, Lund University, Lund, Sweden.
Carl
C
Högberg
Department of Clinical Genetics, Lund University, Lund, Sweden.
Marianne
M
Rissler
Hematology Research Unit Helsinki, University of Helsinki and Comprehensive Cancer Center, Helsinki University Central Hospital, Helsinki, Finland.
Kimmo
K
Porkka
Department of Internal Medicine, University of Gothenburg, Gothenburg, Sweden; and.
Hans
H
Wadenvik
Hematology Research Unit Helsinki, University of Helsinki and Comprehensive Cancer Center, Helsinki University Central Hospital, Helsinki, Finland.
Satu
S
Mustjoki
Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
Johan
J
Richter
Department of Clinical Genetics, Lund University, Lund, Sweden.
Marcus
M
Järås
Department of Clinical Genetics, Lund University, Lund, Sweden.
Thoas
T
Fioretos
D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D053577:Interleukin-1 Receptor Accessory Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000912:Antibodies, Neoplasm; C507765:IL1RAP protein, human; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D009363:Neoplasm Proteins