The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma

Cinzia Fionda, Maria Pia Abruzzese, Alessandra Zingoni, Francesca Cecere, Elisabetta Vulpis, Giovanna Peruzzi, Alessandra Soriani, Rosa Molfetta, Rossella Paolini, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Angela Santoni, Marco Cippitelli

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)23609-23630
Number of pages22
JournalOncotarget
Volume6
Issue number27
DOIs
Publication statusPublished - 2015

Fingerprint

Multiple Myeloma
Natural Killer Cells
Ligands
Transcription Factors
Small Interfering RNA
Ikaros Transcription Factor
Up-Regulation
Gene Expression
Plasma Cells
Pharmaceutical Preparations
Genes
Down-Regulation
Cell Line
Neoplasms
Proteins

Keywords

  • DNAM-1Ls
  • IMiDs
  • Multiple myeloma
  • Natural killer
  • NKG2DLs

ASJC Scopus subject areas

  • Oncology

Cite this

Fionda, C., Abruzzese, M. P., Zingoni, A., Cecere, F., Vulpis, E., Peruzzi, G., ... Cippitelli, M. (2015). The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma. Oncotarget, 6(27), 23609-23630. https://doi.org/10.18632/oncotarget.4603

The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma. / Fionda, Cinzia; Abruzzese, Maria Pia; Zingoni, Alessandra; Cecere, Francesca; Vulpis, Elisabetta; Peruzzi, Giovanna; Soriani, Alessandra; Molfetta, Rosa; Paolini, Rossella; Ricciardi, Maria Rosaria; Petrucci, Maria Teresa; Santoni, Angela; Cippitelli, Marco.

In: Oncotarget, Vol. 6, No. 27, 2015, p. 23609-23630.

Research output: Contribution to journalArticle

Fionda, C, Abruzzese, MP, Zingoni, A, Cecere, F, Vulpis, E, Peruzzi, G, Soriani, A, Molfetta, R, Paolini, R, Ricciardi, MR, Petrucci, MT, Santoni, A & Cippitelli, M 2015, 'The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma', Oncotarget, vol. 6, no. 27, pp. 23609-23630. https://doi.org/10.18632/oncotarget.4603
Fionda, Cinzia ; Abruzzese, Maria Pia ; Zingoni, Alessandra ; Cecere, Francesca ; Vulpis, Elisabetta ; Peruzzi, Giovanna ; Soriani, Alessandra ; Molfetta, Rosa ; Paolini, Rossella ; Ricciardi, Maria Rosaria ; Petrucci, Maria Teresa ; Santoni, Angela ; Cippitelli, Marco. / The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma. In: Oncotarget. 2015 ; Vol. 6, No. 27. pp. 23609-23630.
@article{6cee18d4abe145f9891e0463ebfcbf56,
title = "The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma",
abstract = "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.",
keywords = "DNAM-1Ls, IMiDs, Multiple myeloma, Natural killer, NKG2DLs",
author = "Cinzia Fionda and Abruzzese, {Maria Pia} and Alessandra Zingoni and Francesca Cecere and Elisabetta Vulpis and Giovanna Peruzzi and Alessandra Soriani and Rosa Molfetta and Rossella Paolini and Ricciardi, {Maria Rosaria} and Petrucci, {Maria Teresa} and Angela Santoni and Marco Cippitelli",
year = "2015",
doi = "10.18632/oncotarget.4603",
language = "English",
volume = "6",
pages = "23609--23630",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "27",

}

TY - JOUR

T1 - The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma

AU - Fionda, Cinzia

AU - Abruzzese, Maria Pia

AU - Zingoni, Alessandra

AU - Cecere, Francesca

AU - Vulpis, Elisabetta

AU - Peruzzi, Giovanna

AU - Soriani, Alessandra

AU - Molfetta, Rosa

AU - Paolini, Rossella

AU - Ricciardi, Maria Rosaria

AU - Petrucci, Maria Teresa

AU - Santoni, Angela

AU - Cippitelli, Marco

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - DNAM-1Ls

KW - IMiDs

KW - Multiple myeloma

KW - Natural killer

KW - NKG2DLs

UR - http://www.scopus.com/inward/record.url?scp=84943409539&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943409539&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.4603

DO - 10.18632/oncotarget.4603

M3 - Article

VL - 6

SP - 23609

EP - 23630

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 27

ER -