Antagonistic actions of IRF4 and BACH2 in regulating Germinal Center B cell fates and promoting Lymphomagenesis

/ABSTRACT Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Thus far, efforts to identify factors that predict survival have been unsuccessful. We found that FL patients with a worse prognosis display an increased expression of IRF4. While IRF4 normally promotes terminal differentiation of B cells to plasma cells, its overexpression in FL B cells dysregulates immune signaling and induces an immunosuppressive microenvironment. Our preliminary data show that IRF4 controls the expression of multiple immune recognition molecules, suggesting its role in modulating the interaction between B and T cells. Additionally, silencing of IRF4 in vitro and in vivo led to memory B cell (MB) transcriptional reprogramming and cell differentiation. At the molecular level, there was an inverse correlation between IRF4 and the MB transcription factor (TF) BACH2, suggesting that their mutual antagonism may dictate cell fate. We hypothesize that IRF4 controls B cell fate in counterbalance with BACH2, and disruption of this mechanism promotes lymphomagenesis. To test our hypothesis, we propose two specific aims. In Aim 1 we will use new transgenic mouse models with overexpression and deletion of irf4 in germinal center B cells to investigate whether and how IRF4 counteracts BACH2 to define B cell fates by integrating single-cell transcriptional/protein (CITE-seq) analysis and DNA-binding (CUT&RUN), the latter to identify IRF4 and BACH2 target genes. In Aim 2 we will perform CITE-seq and CUT&RUN of malignant B cells from the transgenic mouse models in Aim 1 to elucidate whether the imbalance between IRF4 and BACH2 promotes lymphomagenesis. These findings will be validated using single cell RNA-seq of human FL tumors. Our study will provide critical insights into normal B cell differentiation as well as lymphomagenesis mediated by IRF4 dysregulation and may uncover novel therapeutic targets. Project Number: 1R21AI187691-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Patrizia Mondello | Institution: MAYO CLINIC ROCHESTER, ROCHESTER, MN | Award Amount: $441,098 | Activity Code: R21 | Study Section: Cancer Genetics Study Section[CG] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18769101A1