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Acute Myeloid Leukemia
The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis
Bauke de Boer,1*° Sofia Sheveleva,1* Katja Apelt,1 Edo Vellenga,1 André B. Mulder,2 Gerwin Huls1 and Jan Jacob Schuringa1
1Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, and 2Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
°Current address: The Finsen Laboratory, Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
*BB and SS contributed equally as co-first authors.
ABSTRACT
Upregulation of the plasma membrane receptor IL1RAP in acute myeloid leukemia (AML) has been reported but its role in the context of the leukemic bone marrow niche is unclear. Here, we studied the signaling events downstream of IL1RAP in relation to leukemogenesis and normal hematopoiesis. High IL1RAP expression was associated with a leukemic GMP- like state, and knockdown of IL1RAP in AML reduced colony-forming capacity. Stimulation with IL1b resulted in the induction of multiple chemokines and an inflammatory secretome via the p38 MAPK and NFkB signaling pathways in IL1RAP-expressing AML cells, but IL1b-induced signaling was dispensable for AML cell proliferation and NFkB-driven survival. IL1RAP was also expressed in stromal cells where IL1b induced expression of inflammatory chemokines and cytokines as well. Intriguingly, the IL1b-induced inflammatory secretome of IL1RAP-expressing AML cells grown on a stromal layer of mesenchymal stem cells affected normal hematopoiesis including hematopoietic stem/progenitor cells while AML cell proliferation was not affected. The addition of Anakinra, an Food and Drug Aministration-approved IL1 receptor antagonist, could reverse this effect. Therefore, blocking the IL1-IL1RAP signaling axis might be a good therapeutic approach to reduce inflammation in the bone marrow niche and thereby promote normal hematopoietic recovery over AML proliferation after chemotherapy.
Introduction
The fate of both acute myeloid leukemia (AML) and normal hematopoietic stem cells (HSC) is critically dependent on interactions with the bone marrow (BM) niche.1-4 Recent data has also suggested that malignant cells can remodel the BM microenvironment into a leukemic BM niche favoring leukemogenesis over normal hematopoiesis.4-6 Plasma membrane (PM) proteins are first in line to respond to signals that arise from the BM niche. One of these PM proteins, inter- leukin-1 receptor accessory protein (IL1RAP), is specifically upregulated in stem/progenitor cells from chronic myeloid leukemia (CML) and AML patients but not on normal CD34+ hematopoietic stem/progenitor cells (HSPC).7-10 This has led to several studies that investigated the targetability of IL1RAP as treatment strategy of chronic myeloid leukemia (CML) and AML,9,11-13 but little is known regarding the cell-intrinsic role of IL1RAP in AML stem/progenitor cells. In addi- tion, the canonical IL1RAP signaling axis in AML with respect to the leukemic BM niche has not been studied extensively.
The IL1 family is part of the innate immunity that regulates local inflammatory responses, and its dysregulation may lead to autoinflammatory diseases often caused by excessive IL1b production.14 The IL1 family consists of seven ligands including IL1α, IL1b, IL18, IL33, IL36α, b and g that can bind different IL1 recep-
Ferrata Storti Foundation
Haematologica 2021 Volume 106(12):3067-3078
Correspondence:
JAN JACOB SCHURINGA
j.j.schuringa@umcg.nl
Received: April 9, 2020. Accepted: October 9, 2020. Pre-published: October 29, 2020.
https://doi.org/10.3324/haematol.2020.254987 ©2021 Ferrata Storti Foundation
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