IL1RAP potentiates multiple oncogenic signaling pathways in AML.

The Journal of Experimental Medicine
Kelly MitchellUlrich Steidl

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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Citations

May 29, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·He-Zhou GuoShan-He Yu
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Sep 10, 2020·Endocrine, Metabolic & Immune Disorders Drug Targets·Sridhar MuthusamiIlangovan Ramachandran

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Methods Mentioned

BETA
flow cytometry
MDS
FACS
xenograft
immunoprecipitation
pulldown
coimmunoprecipitation
FRET
flow
Fluorescence

Software Mentioned

FlowJo
ImageJ
GraphPad Prism
FACSDiva
Adobe Photoshop
GraphPad

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