Wstf degradation through nuclear autophagy promotes inflammatory responses in primary myelofibrosis: Implications for XPO1 inhibitor-based therapeutic strategies

Abstract

Abstract Background: Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by persistent inflammation. Nuclear autophagy, activated in chronic inflammatory states, selectively degrades the chromatin remodeling factor WSTF, thereby promoting the perpetuation and amplification of inflammatory responses. Given the potential link between WSTF dysregulation and disease progression, we investigated the role of WSTF in PMF pathogenesis and its possible association with the efficacy of XPO1 inhibitors. Methods: We analyzed bone marrow samples from 20 patients with overt-PMF to assess WSTF expression levels using immunohistochemistry and quantitative PCR. Correlations between WSTF expression, inflammatory markers (e.g., TNF-α, IL-6), and clinical progression were evaluated. Additionally, in vitro studies were conducted to examine the impact of WSTF modulation on XPO1 inhibitor sensitivity in PMF-derived cell lines. Results: WSTF expression was significantly reduced in overt-PMF patients compared to pre-PMF, correlating with elevated inflammatory cytokine levels and advanced disease stage. Patients with lower WSTF exhibited worse prognosis, including increased bone marrow fibrosis. Mechanistically, WSTF loss exacerbated JAK-STAT and NF-κB signaling, sustaining inflammation. Notably, WSTF-deficient cells showed heightened sensitivity to XPO1 inhibition, suggesting a synergistic therapeutic vulnerability. Conclusion: Our findings implicate WSTF degradation via nuclear autophagy as a key driver of PMF-associated inflammation. The inverse relationship between WSTF and XPO1 inhibitor efficacy highlights its potential as a predictive biomarker and therapeutic target. Combining XPO1 inhibitors with strategies to restore WSTF function may offer a novel approach to mitigate inflammation and improve outcomes in PMF.