The TNF family member receptor activator for NF-κB ligand (RANKL) and its 
receptors RANK and osteoprotegerin are key regulators of bone remodeling but 
also influence cellular functions of tumor and immune effector cells. In this 
work, we studied the involvement of RANK-RANKL interaction in NK cell-mediated 
immunosurveillance of acute myeloid leukemia (AML). Substantial levels of RANKL 
were found to be expressed on leukemia cells in 53 of 78 (68%) investigated 
patients. Signaling via RANKL into the leukemia cells stimulated their metabolic 
activity and induced the release of cytokines involved in AML pathophysiology. 
In addition, the immunomodulatory factors released by AML cells upon RANKL 
signaling impaired the anti-leukemia reactivity of NK cells and induced RANK 
expression, and NK cells of AML patients displayed significantly upregulated 
RANK expression compared with healthy controls. Treatment of AML cells with the 
clinically available RANKL Ab Denosumab resulted in enhanced NK cell 
anti-leukemia reactivity. This was due to both blockade of the release of 
NK-inhibitory factors by AML cells and prevention of RANK signaling into NK 
cells. The latter was found to directly impair NK anti-leukemia reactivity with 
a more pronounced effect on IFN-γ production compared with cytotoxicity. 
Together, our data unravel a previously unknown function of the RANK-RANKL 
molecule system in AML pathophysiology as well as NK cell function and suggest 
that neutralization of RANKL with therapeutic Abs may serve to reinforce NK cell 
reactivity in leukemia patients.