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VALERIA CANCILA

MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells

  • Authors: Matis, Serena; Grazia Recchia, Anna; Colombo, Monica; Cardillo, Martina; Fabbi, Marina; Todoerti, Katia; Bossio, Sabrina; Fabris, Sonia; Cancila, Valeria; Massara, Rosanna; Reverberi, Daniele; Emionite, Laura; Cilli, Michele; Cerruti, Giannamaria; Salvi, Sandra; Bet, Paola; Pigozzi, Simona; Fiocca, Roberto; Ibatici, Adalberto; Angelucci, Emanuele; Gentile, Massimo; Monti, Paola; Menichini, Paola; Fronza, Gilberto; Torricelli, Federica; Ciarrocchi, Alessia; Neri, Antonino; Fais, Franco; Tripodo, Claudio; Morabito, Fortunato; Ferrarini, Manlio; Cutrona, Giovanna
  • Publication year: 2022
  • Type: Articolo in rivista
  • OA Link: http://hdl.handle.net/10447/578967

Abstract

Chronic lymphocytic leukemia (CLL) cells express the interleukin-23 receptor (IL-23R) chain, but the expression of the complementary IL-12R(31 chain requires cell stimulation via surface CD40 molecules (and not via the B-cell receptor [BCR]). This stimulation induces the expression of a heterodimeric functional IL-23R complex and the secretion of IL-23, initiating an autocrine loop that drives leukemic cell expansion. Based on the observation in 224 untreated Binet stage A patients that the cases with the lowest miR-146b-5p concentrations had the shortest time to first treatment (TTFT), we hypothesized that miR-146b-5p could negatively regulate IL-12R(31 side chain expression and clonal expansion. Indeed, miR-146b-5p significantly bound to the 3 '-UTR region of the IL-12R(31 mRNA in an in vitro luciferase assay. Downregulation of miR-146b-5p with specific miRNA inhibitors in vitro led to the upregulation of the IL-12R(31 side chain and expression of a functional IL-23R complex similar to that observed after stimulation of the CLL cell through the surface CD40 molecules. Expression of miR-146b-5p with miRNA mimics in vitro inhibited the expression of the IL-23R complex after stimulation with CD40L. Administration of a miR-146b-5p mimic to NSG mice, successfully engrafted with CLL cells, caused tumor shrinkage, with a reduction of leukemic nodules and of IL-12R(31-positive CLL cells in the spleen. Our findings indicate that IL-12R(31 expression, a crucial checkpoint for the functioning of the IL-23 and IL-23R complex loop, is under the control of miR-146b-5p, which may represent a potential target for therapy since it contributes to the CLL pathogenesis. This trial is registered at www.clinicaltrials.gov as NCT00917540.