LAUSR

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. We studied the signaling events downstream of IL1RAP in relation to leukemogenesis and healthy hematopoiesis. IL1RAP was significantly upregulated across various AML subtypes and was expressed on the outer membrane, whereby high IL1RAP expression was associated with a leukemic GMP-like state. Stimulation with IL1-beta resulted in the induction of multiple chemokines and an inflammatory secretome via the p38 MAPK and NF-kB signaling pathways. IL1-beta-induced signaling through IL1RAP was dispensable for AML cell proliferation and NF-kB-driven survival. IL1RAP was also expressed in stromal cells where IL1-beta-induced expression of inflammatory chemokines and cytokines as well. Intriguingly, the IL1-beta-induced inflammatory secretome of AML cells grown on stroma affected the proliferation of healthy hematopoietic cells while AML cell proliferation was much less affected. The addition of Anakinra, an FDA-approved IL1 receptor antagonist, could partially reverse this effect. 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.