IL1RAP potentiates multiple oncogenic signaling pathways in AML

Kelly Mitchell, Laura Barreyro, Tihomira I. Todorova, Samuel J. Taylor, Iléana Antony-Debré, Swathi-Rao Narayanagari, Luis A. Carvajal, Joana Leite, Zubair Piperdi, Gopichand Pendurti, Ioannis Mantzaris, Elisabeth M. Paietta, Amit K. Verma, Kira Gritsman, Ulrich G. Steidl

Research output: Contribution to journalArticle

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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 proproliferative 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.

Original languageEnglish (US)
Pages (from-to)1709-1727
Number of pages19
JournalJournal of Experimental Medicine
Volume215
Issue number6
DOIs
StatePublished - Jun 1 2018

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Interleukin-1 Receptor Accessory Protein
Acute Myeloid Leukemia
Interleukin-1 Receptors
Receptor Protein-Tyrosine Kinases
Protein Transport
Myeloid Cells
RNA Interference
Stem Cells
Antibodies

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

IL1RAP potentiates multiple oncogenic signaling pathways in AML. / Mitchell, Kelly; Barreyro, Laura; Todorova, Tihomira I.; Taylor, Samuel J.; Antony-Debré, Iléana; Narayanagari, Swathi-Rao; Carvajal, Luis A.; Leite, Joana; Piperdi, Zubair; Pendurti, Gopichand; Mantzaris, Ioannis; Paietta, Elisabeth M.; Verma, Amit K.; Gritsman, Kira; Steidl, Ulrich G.

In: Journal of Experimental Medicine, Vol. 215, No. 6, 01.06.2018, p. 1709-1727.

Research output: Contribution to journalArticle

Mitchell, K, Barreyro, L, Todorova, TI, Taylor, SJ, Antony-Debré, I, Narayanagari, S-R, Carvajal, LA, Leite, J, Piperdi, Z, Pendurti, G, Mantzaris, I, Paietta, EM, Verma, AK, Gritsman, K & Steidl, UG 2018, 'IL1RAP potentiates multiple oncogenic signaling pathways in AML', Journal of Experimental Medicine, vol. 215, no. 6, pp. 1709-1727. https://doi.org/10.1084/jem.20180147
Mitchell K, Barreyro L, Todorova TI, Taylor SJ, Antony-Debré I, Narayanagari S-R et al. IL1RAP potentiates multiple oncogenic signaling pathways in AML. Journal of Experimental Medicine. 2018 Jun 1;215(6):1709-1727. https://doi.org/10.1084/jem.20180147
Mitchell, Kelly ; Barreyro, Laura ; Todorova, Tihomira I. ; Taylor, Samuel J. ; Antony-Debré, Iléana ; Narayanagari, Swathi-Rao ; Carvajal, Luis A. ; Leite, Joana ; Piperdi, Zubair ; Pendurti, Gopichand ; Mantzaris, Ioannis ; Paietta, Elisabeth M. ; Verma, Amit K. ; Gritsman, Kira ; Steidl, Ulrich G. / IL1RAP potentiates multiple oncogenic signaling pathways in AML. In: Journal of Experimental Medicine. 2018 ; Vol. 215, No. 6. pp. 1709-1727.
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