Immune escape of multiple myeloma cells results from low miR29b and the ensuing epigenetic silencing of proteasome genes

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dc.contributor.authorLeone, Patrizia
dc.contributor.authorMalerba, Eleonora
dc.contributor.authorPrete, Marcella
dc.contributor.authorSolimando, Antonio G.
dc.contributor.authorCroci, Giorgio A.
dc.contributor.authorDitonno, Paolo
dc.contributor.authorTucci, Marco
dc.contributor.authorSusca, Nicola
dc.contributor.authorDerakhshani, Afshin
dc.contributor.authorDufour, Antoine
dc.contributor.authorDe Re, Valli
dc.contributor.authorSilvestris, Nicola
dc.contributor.authorRacanelli, Vito
dc.date.accessioned2024-04-28T00:04:56Z
dc.date.available2024-04-28T00:04:56Z
dc.date.issued2024-04-23
dc.date.updated2024-04-28T00:04:55Z
dc.description.abstractAbstract Background Activation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies. Methods This study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads. Results We show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival. Conclusions Altogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.
dc.identifier.citationBiomarker Research. 2024 Apr 23;12(1):43
dc.identifier.urihttps://doi.org/10.1186/s40364-024-00592-y
dc.identifier.urihttps://hdl.handle.net/1880/118574
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dc.titleImmune escape of multiple myeloma cells results from low miR29b and the ensuing epigenetic silencing of proteasome genes
dc.typeJournal Article
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