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Blood, 9 April 2009, Vol. 113, No. 15, pp. 3503-3511.
Prepublished online as a Blood First Edition Paper on December 19, 2008; DOI 10.1182/blood-2008-08-173914.
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Submitted August 13, 2008
Accepted December 14, 2008
ATM-ATR dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK cell susceptibility and is associated with a senescent phenotype
Alessandra Soriani*, Alessandra Zingoni, Cristina Cerboni, Maria Luisa Iannitto, Maria Rosaria Ricciardi, Valentina Di Gialleonardo, Marco Cippitelli, Cinzia Fionda, Maria Teresa Petrucci, Anna Guarini, Robin Foa, and Angela Santoni
Department of Experimental Medicine, Instituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" University of Rome, Rome, Italy
Division of Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Rome, Italy
Regina Elena Cancer Institute, Centro Ricera Sperimentale, Rome, Italy
* Corresponding author; email: alessandra.soriani{at}uniroma1.it.
Numerous evidences support a role for natural killer (NK) cells in controlling the progression of multiple myeloma (MM), a malignancy characterized by an abnormal plasma cell proliferation in the bone marrow (BM). Induction of DNA damage response has been recently shown capable of enhancing NKG2D ligand (NKG2DL) expression, but nothing is known about DNAM-1 ligand (DNAM-1L) regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan and bortezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK cell degranulation, being the NKG2D and DNAM-1 receptors the major triggering molecules. Similar data were also obtained using ex vivo primary plasma cells derived from MM patients. Drug-induced DNAM-1 and NKG2D ligand expression was abolished following treatment with the ATM and ATR pharmacological inhibitors caffeine and KU-55933, and was preferentially associated with senescent cells arrested in the G2 phase of the cell cycle.
Altogether, our findings have identified a common pathway that can trigger the up-regulation of different NK cell activating ligands and suggest that NK cells represent an immunosurveillance mechanism towards cells undergoing stress-induced senescent programs.
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