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

Serena Matis, Anna Grazia Recchia, Monica Colombo, Martina Cardillo, Marina Fabbi, Katia Todoerti, Sabrina Bossio, Sonia Fabris, Valeria Cancila, Rosanna Massara, Daniele Reverberi, Laura Emionite, Michele Cilli, Giannamaria Cerruti, Sandra Salvi, Paola Bet, Simona Pigozzi, Roberto Fiocca, Adalberto Ibatici, Emanuele AngelucciMassimo Gentile, Paola Monti, Paola Menichini, Gilberto Fronza, Federica Torricelli, Alessia Ciarrocchi, Antonino Neri, Franco Fais, Claudio Tripodo, Fortunato Morabito, Manlio Ferrarini, Giovanna Cutrona

Research output: Contribution to journalArticlepeer-review


Chronic lymphocytic leukemia (CLL) cells express the interleukin-23 receptor (IL-23R) chain, but the expression of the complementary IL-12Rβ1 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-12Rβ1 side chain expression and clonal expansion. Indeed, miR-146b-5p significantly bound to the 3-UTR region of the IL-12Rβ1 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-12Rβ1 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-12Rβ1–positive CLL cells in the spleen. Our findings indicate that IL-12Rβ1 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.

Original languageEnglish
Pages (from-to)5593-5612
Number of pages20
JournalBlood advances
Issue number20
Publication statusPublished - Oct 25 2022

ASJC Scopus subject areas

  • Hematology


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