MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells
•Low concentrations of miR-146b-5p have an adverse prognostic impact in CLL patients.•miR-146b-5p controls IL-23 stimulation of CLL cells by negatively regulating the expression of the IL-12Rβ1 chain of the IL-23R complex. [Display omitted] Chronic lymphocytic leukemia (CLL) cells express the interl...
Gespeichert in:
Veröffentlicht in: | Blood advances 2022-10, Vol.6 (20), p.5593-5612 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | •Low concentrations of miR-146b-5p have an adverse prognostic impact in CLL patients.•miR-146b-5p controls IL-23 stimulation of CLL cells by negatively regulating the expression of the IL-12Rβ1 chain of the IL-23R complex.
[Display omitted]
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. |
---|---|
ISSN: | 2473-9529 2473-9537 2473-9537 |
DOI: | 10.1182/bloodadvances.2021005726 |