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.
There is much evidence to 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, the NKG2D and DNAM-1 receptors being 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 after treatment with the ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) pharmacologic 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 toward cells undergoing stress-induced senescent programs.
Soriani
Alessandra
A
Department of Experimental Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy. alessandra.soriani@uniroma1.it
Zingoni
Alessandra
A
Cerboni
Cristina
C
Iannitto
Maria Luisa
ML
Ricciardi
Maria Rosaria
MR
Di Gialleonardo
Valentina
V
Cippitelli
Marco
M
Fionda
Cinzia
C
Petrucci
Maria Teresa
MT
Guarini
Anna
A
Foà
Robin
R
Santoni
Angela
A
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D058851:GPI-Linked Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects*; D008558:Melphalan / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1
C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000903:Antibiotics, Antineoplastic; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000098862:T Lineage-Specific Activation Antigen 1; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines; D010726:Phosphodiesterase Inhibitors; D011753:Pyrones; D025521:Tumor Suppressor Proteins; C423230:ULBP2 protein, human; D002110:Caffeine; D004317:Doxorubicin; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D008558:Melphalan