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.

Matis, S., Grazia Recchia, A., Colombo, M., Cardillo, M., Fabbi, M., Todoerti, K., et al. (2022). MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells. BLOOD ADVANCES, 6(20), 5593-5612 [10.1182/bloodadvances.2021005726].

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

Cancila, Valeria;Tripodo, Claudio;
2022-10-25

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.
Settore MED/08 - Anatomia Patologica
Settore MED/05 - Patologia Clinica
Matis, S., Grazia Recchia, A., Colombo, M., Cardillo, M., Fabbi, M., Todoerti, K., et al. (2022). MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells. BLOOD ADVANCES, 6(20), 5593-5612 [10.1182/bloodadvances.2021005726].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/578967
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