# Intraclonal Enrichment of IL-23 Receptor Complex Expression in the Proliferative Fraction of Chronic Lymphocytic Leukemia

## TL;DR

This study shows that a specific group of chronic lymphocytic leukemia cells expresses more IL-23 receptors, suggesting a new potential target for treatment.

## Contribution

The paper identifies an intraclonal bias toward IL-23 receptor complex expression in proliferative CLL cells.

## Key findings

- IL-12Rβ1 is enriched in proliferative CLL cells and correlates with higher IL-23R complex expression.
- Activation increases IL-23R and IL-12Rβ1 but not IL-12Rβ2 surface expression, favoring IL-23R complex formation.
- Proliferative CLL cells show stronger induction of IL-23R complex compared to resting cells after activation.

## Abstract

Chronic lymphocytic leukemia (CLL) is a dynamic malignancy in which intraclonal subfractions differ in activation history and responsiveness to microenvironmental signals. Here, we investigated the expression and inducibility of IL-12 family receptor subunits (IL-23R, IL-12Rβ1, IL-12Rβ2) and the related receptor complexes in recirculating CLL cells, with a focus on CXCR4/CD5-defined fractions: the proliferative fraction (PF; CXCR4dim/CD5bright; most recently divided, tissue-emigrated cells) and the resting fraction (RF; CXCR4bright/CD5dim; older, quiescent cells). At baseline, IL-12Rβ1 was enriched in the PF and was associated with a higher proportion of cells expressing IL-23R and IL-12R receptor complexes. Concomitantly, RT-qPCR disclosed higher IL-12Rβ1 mRNA levels. Following antigen-independent activation with CpG or CpG + IL-15, there was a marked increase in IL-23R and IL-12Rβ1 but not in IL-12Rβ2 surface expression, resulting in preferential upregulation of the IL-23R complex over the IL-12R complex. Fraction-specific analyses showed stronger induction of IL-23R and IL-23R complex expression in PF compared with RF. These findings identify an intraclonal bias toward IL-23 responsiveness in the CLL cells with a phenotype of recently divided, tissue-emigrated cells and suggest the IL-23/IL-23R axis as a potential therapeutic target.