The USP35-CXCR3 Axis plays an oncogenic role in JeKo-1 mantle cell lymphoma cells.

In B cells, the chemokine receptor CXCR3 is expressed only by a subset of B cells. However, CXCR3 is highly expressed in a rare type of B-cell lymphoma known as Mantle Cell Lymphoma (MCL) and CXCR3 inhibitor impairs proliferation and induces apoptosis in the MCL cell line JeKo-1. Despite this, the mechanism responsible for maintaining high levels of CXCR3 in MCL cells remains unclear. In this study, we assessed CXCR3 expression and amplification in MCL samples and confirmed that CXCR3 is overexpressed in MCL tissues. We also observed that CXCR3 amplification is present in a small portion of MCL patients and is associated with MCL classification. We then screened ubiquitin-specific proteases (USPs) that might control the degradation of CXCR3 protein. Our investigation revealed that USP35 acts as a potent stabilizer of CXCR3 protein. Knockdown of USP35 substantially reduced the CXCR3 protein levels in JeKo-1 cells, resulting in reduced cell viability, cell cycle arrest, increased apoptosis, and mitigated migration and invasion in these cells. At the molecular level, USP35 deubiquitinates and stabilizes CXCR3. USP35 deficiency attenuated the activation of the JAK1/STAT1 pathway and reduced the expression of β-catenin and c-Myc in JeKo-1 cells. Furthermore, we observed that overexpression of CXCR3 rescued the impaired tumorigenicity of USP35-deficient JeKo-1 cells, and the mechanism may be related to the fact that USP35 promotes CXCR3 deubiquitination to stabilize its expression. These findings collectively demonstrate the oncogenic role of the USP35-CXCR3 axis in JeKo-1 MCL cells.