NDLI: Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Schmiedel, Benjamin Joachim Steinbacher, Julia Wende, Constantin Maximilian Schneider, Pascal Grosse-Hovest, Ludger Azuma, Miyuki Nuebling, Tina Salih, Helmut Rainer Malinovska, Alexandra
Description	Country affiliation: Germany Author Affiliation: Schmiedel BJ ( Department of Hematology and Oncology, Eberhard Karls University, 72076 Tuebingen, Germany.)
Abstract	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-Î³ 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.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	2
Volume Number	190
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2013-01-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Killer Cells, Natural Immunology Metabolism Leukemia, Myeloid, Acute Rank Ligand Adolescent Antibodies, Monoclonal, Humanized Pharmacology Cell Line Denosumab Gene Expression Regulation, Leukemic Immunomodulation Drug Effects Genetics Protein Binding Antagonists & Inhibitors Receptor Activator Of Nuclear Factor-kappa B Signal Transduction Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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