LSCs but not HSCs exploit IL-1 signaling in the CML BM microenvironment. Increased IL-1 levels and IL-1R1 and IL-1RAP overexpression confer a selective advantage on LSCs over HSCs in the leukemic BM microenvironment. Targeting of IL-1 signaling via antibody and antagonist (IL-1RA) therapy eliminates the proliferative advantage, reshapes the microenvironment, and favors elimination of LSCs by effector cells and TKIs. Ab, antibody; TKIs, tyrosine kinase inhibitors.