# Translational Insights into Interferon Alpha’s Effects on Immunomolecular Dynamics in Philadelphia-Negative Myeloproliferative Neoplasms

## TL;DR

This study explores how interferon alpha affects immune responses and gene activity in blood cancer patients, revealing patterns that could help personalize treatment.

## Contribution

The study identifies dynamic immunomolecular changes during interferon alpha therapy in myeloproliferative neoplasms, suggesting potential biomarkers for treatment response.

## Key findings

- Prolonged interferon alpha exposure reduces pro-inflammatory cytokines and downregulates STAT1/STAT3 signaling.
- Intermediate treatment exposure is linked to transient TH2/regulatory cytokine peaks and upregulation of genes like CXCL10, SOCS3, and TNFAIP3.
- Functional correlations between cytokine and gene expression patterns suggest immune reprogramming by interferon alpha.

## Abstract

Patients with chronic blood cancers called myeloproliferative neoplasms (MPNs) can benefit from a therapy based on interferon alpha, which helps the immune system fight disease. However, we still do not fully understand how this treatment works at the molecular level, or how to predict who will respond best. In this study, we analyzed blood samples from patients treated with interferon alpha to investigate changes in immune signals and gene activity over time. We found a progressive decrease in inflammation-related molecules and changes in genes involved in immune regulation, cell survival, and blood cell production. These results suggest that interferon gradually reshapes the immune system and may help control the disease by reducing inflammation and promoting cell death in abnormal blood cells. Our findings may help identify new biomarkers to personalize treatment and monitor its effectiveness in future patients.

Background/Objectives: Interferon alpha (IFNα) remains a cornerstone in the management of Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPNs), yet its immunomolecular impact over time is not fully elucidated. The aim of the study was to explore how IFNα therapy dynamically reshapes immune and gene profiles in Ph-neg MPNs and assess their potential as treatment-related biomarkers. Methods: This single-center, prospective, observational study included a translational substudy conducted within a previously established clinical cohort of 44 IFNα-treated patients, selecting a representative subset of 18 individuals stratified by treatment duration. Cytokine profiling (ELISA) and gene expression (RT-qPCR) analysis were performed using plasma and peripheral blood mononuclear cells (PBMCs), respectively. Results: Patients with prolonged exposure showed reduced pro-inflammatory cytokines and downregulation of inflammatory-signalling STAT1/STAT3 expression. In contrast, those with intermediate exposure exhibited transient TH2/regulatory cytokine peaks and upregulation of immunomodulatory genes such as CXCL10, SOCS3, and TNFAIP3. Spearman correlations revealed functional associations between cytokine and gene expression patterns including notable links such as STAT1–IL-13 and MYB–IL-13. Conclusions: These results describe a sequential immune reprogramming driven by IFNα, supporting the development of dynamic immunomolecular biomarkers of response in Ph-neg MPNs.