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J Exp Med. 2018 Jun 4;215(6):1709-1727. doi: 10.1084/jem.20180147. Epub 2018 May 17.

IL1RAP potentiates multiple oncogenic signaling pathways in AML.

Author information

1
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY.
2
Department of Medicine (Oncology), Division of Hemato-Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY.
3
Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY.
4
Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY.
5
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY ulrich.steidl@einstein.yu.edu.

Abstract

The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and pro-proliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.

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