The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma.
Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms. Indeed, shRNA knockdown of IKZF1 or IKZF3 expression was both necessary and sufficient for the upregulation of MICA and PVR/CD155 expression, suggesting that these transcription factors can repress these genes; accordingly, the direct interaction and the negative role of IKZF1 and IKZF3 proteins on MICA and PVR/CD155 promoters were demonstrated. Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells.Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells.
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Cinzia
C
Fionda
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Maria Pia
MP
Abruzzese
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Alessandra
A
Zingoni
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Francesca
F
Cecere
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Elisabetta
E
Vulpis
Istituto Italiano di Tecnologia, CLNS@Sapienza, Sapienza University of Rome, Rome, Italy.
Giovanna
G
Peruzzi
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Alessandra
A
Soriani
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Rosa
R
Molfetta
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Rossella
R
Paolini
Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
Maria Rosaria
MR
Ricciardi
Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
Maria Teresa
MT
Petrucci
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.|Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, Italy.
Angela
A
Santoni
Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Marco
M
Cippitelli
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007155:Immunologic Factors / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology*; D000077269:Lenalidomide; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011991:Receptors, Virus / Q000096:biosynthesis / Q000235:genetics*; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D000098862:T Lineage-Specific Activation Antigen 1; D000099218:Interferon Regulatory Factor-4
D020533:Angiogenesis Inhibitors; D000945:Antigens, Differentiation, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D051740:Ikaros Transcription Factor; D007155:Immunologic Factors; D050835:Interferon Regulatory Factors; D000077269:Lenalidomide; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011991:Receptors, Virus; D013792:Thalidomide; D000098862:T Lineage-Specific Activation Antigen 1; D000099218:Interferon Regulatory Factor-4; C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C066100:poliovirus receptor
DNAM-1Ls; IMiDs; NKG2DLs; multiple myeloma; natural killer