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

TY - JOUR

T1 - IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models

AU - Ågerstam, Helena

AU - Hansen, Nils

AU - von Palffy, Sofia

AU - Sandén, Carl

AU - Reckzeh, Kristian

AU - Karlsson, Christine

AU - Lilljebjörn, Henrik

AU - Landberg, Niklas

AU - Askmyr, Maria

AU - Högberg, Carl

AU - Rissler, Marianne

AU - Porkka, Kimmo

AU - Wadenvik, Hans

AU - Mustjoki, Satu

AU - Richter, Johan

AU - Järås, Marcus

AU - Fioretos, Thoas

N1 - © 2016 by The American Society of Hematology.

PY - 2016/12/8

Y1 - 2016/12/8

N2 - 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 (CD341CD382) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NFkB 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.

AB - 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 (CD341CD382) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NFkB 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.

KW - Animals

KW - Antibodies, Neoplasm/pharmacology

KW - Female

KW - Humans

KW - Interleukin-1/metabolism

KW - Interleukin-1 Receptor Accessory Protein/antagonists & inhibitors

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Neoplasm Proteins/antagonists & inhibitors

KW - Neoplastic Stem Cells/metabolism

KW - Xenograft Model Antitumor Assays

U2 - 10.1182/blood-2015-11-679985

DO - 10.1182/blood-2015-11-679985

M3 - Journal article

C2 - 27621309

SN - 0006-4971

VL - 128

SP - 2683

EP - 2693

JO - Blood

JF - Blood

IS - 23

ER -