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

Ågerstam, Helena LU ; Hansen, Nils LU ; von Palffy, Sofia LU ; Sandén, Carl LU ; Reckzeh, Kristian LU ; Karlsson, Christine LU ; Lilljebjörn, Henrik LU ; Landberg, Niklas LU ; Askmyr, Maria LU and Högberg, Carl LU , et al. (2016) In Blood 128(23). p.2683-2693
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... (More)

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.

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publication status
published
subject
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Blood
volume
128
issue
23
pages
2683 - 2693
publisher
American Society of Hematology
external identifiers
  • scopus:85015673060
ISSN
1528-0020
DOI
10.1182/blood-2015-11-679985
language
English
LU publication?
yes
id
6c5004c7-7e9c-4990-87e3-b5ba1032dafc
date added to LUP
2017-01-30 09:55:02
date last changed
2017-10-31 08:15:45
@article{6c5004c7-7e9c-4990-87e3-b5ba1032dafc,
  abstract     = {<p>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.</p>},
  author       = {Ågerstam, Helena and Hansen, Nils and von Palffy, Sofia and Sandén, Carl and Reckzeh, Kristian and Karlsson, Christine and Lilljebjörn, Henrik and Landberg, Niklas and Askmyr, Maria and Högberg, Carl and Rissler, Marianne and Porkka, Kimmo and Wadenvik, Hans and Mustjoki, Satu and Richter, Johan and Järås, Marcus and Fioretos, Thoas},
  issn         = {1528-0020},
  language     = {eng},
  month        = {12},
  number       = {23},
  pages        = {2683--2693},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models},
  url          = {http://dx.doi.org/10.1182/blood-2015-11-679985},
  volume       = {128},
  year         = {2016},
}