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

doi:10.18632/oncotarget.4603

Cited by 79 publications

(93 citation statements)

References 64 publications

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“…The importance of enhancer-mediated CDCA7L expression in MM demonstrates the potential of translating basic mechanistic insights of tumour initiation towards development of therapeutic strategies. Indeed, downregulation of IRF4 in MM has been shown to be central to potent antitumour activities by immunomodulatory drugs1819. Similarly, bromodomain inhibition of the transcriptional co-activators CBP/EP300 is seen as a therapeutic strategy to target the IRF4 network in MM20.…”

Section: Discussionmentioning

confidence: 99%

Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression

Johnson

Weinhold

et al. 2016

Nat Commun

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Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10−25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10−36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM.

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Section: Discussionmentioning

confidence: 99%

Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression

Johnson

Weinhold

et al. 2016

Nat Commun

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“…8 This notion has spurred great interest in developing strategies aimed at stimulating NK cell-mediated functions for MM immunotherapy. [9][10][11][12] The ability of anticancer chemotherapy and radiotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of immunogenic cell death (ICD) and release of DAMPs, including heat shock proteins (HSPs), high-mobility group box 1 proteins (HMGB1), ATP and the endoplasmic reticulum (ER) chaperone calreticulin. 13,14 In this context, both HSP70 and HMGB1 appear to exert an immunostimulatory activity by promoting DC maturation through TLR4, which, in turn, leads to the induction of antigen-specific T cell-mediated antitumor immune responses.…”

Section: Introductionmentioning

confidence: 99%

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis

et al. 2017

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Exosomes are a class of nanovesicles formed and released through the late endosomal compartment and represent an important mode of intercellular communication. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Here, we investigated whether genotoxic stress could promote the release of exosomes from multiple myeloma (MM) cells and studied the immunomodulatory properties they exert on NK cells, a major component of the antitumor immune response playing a key role in the immunosurveillance of MM. Our findings show that melphalan, a genotoxic agent used in MM therapy, significantly induces an increased exosome release from MM cells. MM cell-derived exosomes are capable of stimulating IFNg production, but not the cytotoxic activity of NK cells through a mechanism based on the activation of NF-kB pathway in a TLR2/ HSP70-dependent manner. Interestingly, HSP70C exosomes are primarily found in the bone marrow (BM) of MM patients suggesting that they might have a crucial immunomodulatory action in the tumor microenvironment. We also provide evidence that the CD56 high NK cell subset is more responsive to exosome-induced IFNg production mediated by TLR2 engagement. All together, these findings suggest a novel mechanism of synergism between chemotherapy and antitumor innate immune responses based on the drug-promotion of nanovesicles exposing DAMPs for innate receptors.

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“…In particular, our group has demonstrated that genotoxic drugs including doxorubicin and melphalan by generating reactive oxygen species (ROS) induce a DNA Damage Response (DDR)-dependent increase of activating NK receptor ligand expression on senescent tumor cells ( 14 ). More recently, we have also proven that expression of the NKG2D and DNAM-1 activating ligands MICA and PVR, is enhanced by immunomodulatory drugs (IMiDs) ( 24 ). It is well known that microtubules influence a variety of cell stress responses and act as coordinators of cell functions in response to stress ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

et al. 2016

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The mechanisms that regulate the expression of the NKG2D and DNAM-1 activating ligands are only partially known, but it is now widely established that their expression is finely regulated at transcriptional, post-transcriptional and post-translational level, and involve numerous stress pathways depending on the type of ligand, stressor, and cell context.We show that treatment of Multiple Myeloma (MM) cells with sub-lethal doses of Vincristine (VCR), an anticancer drug that inhibits the assembly of microtubules, stimulates the expression of NKG2D and DNAM-1 activating ligands, rendering these cells more susceptible to NK cell-mediated killing. Herein, we focused our attention on the identification of the signaling pathways leading to de novo surface expression of ULBP-1, and to MICA and PVR upregulation on VCR-treated MM cells, both at protein and mRNA levels.We found that p38MAPK differentially regulates drug-dependent ligand upregulation at transcriptional and post-transcriptional level. More specifically, we observed that ULBP-1 expression is attributable to both increased transcriptional activity mediated by ATM-dependent p53 activation, and enhanced mRNA stability; while the p38-activated E2F1 transcription factor regulates MICA and PVR mRNA expression. All together, our findings reveal a previously unrecognized activity of VCR as anticancer agent, and indicate that in addition to its established ability to arrest cell growth, VCR can also modulate the expression of NKG2D and DNAM-1 activating ligand on tumor cells and thus promoting NK cell-mediated immunosurveillance.

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

Cited by 79 publications

References 64 publications

Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression

Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis

p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

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