Role of Histone Deacetylase9 in B cell Non-Hodgkin's Lymphoma

• Applicant: Dr. Tino Schenk
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564501154

Deregulation of histone deacetylases (HDACs) through aberrant expression or activity is implicated in the development and maintenance of numerous hematologic malignancies. Although members of the HDAC family are promising drug targets, limited understanding of their individual functions and challenges in achieving specific inhibition often hinder the effective use of HDAC inhibitors in clinical applications. Among the HDAC family, HDAC9 is one of the least studied, and its role in lymphoma pathogenesis remains largely unknown. Experimental data suggest that HDAC9 plays a functional role in normal B-cell development and maturation, with its misregulation leading to disrupted B-cell differentiation and the progression to mature B-cell neoplasms. We hypothesize that the misregulated p38MAPK/MEF2C pathway drives aberrant expression of HDAC9 in B-cell non-Hodgkin lymphomas (B-NHL), which in turn promotes high levels of BCL6 and contributes to p53 loss. HDAC9 inhibition appears to counteract this mechanism and can be monitored using a novel technology capable of measuring specific BCL6 and p53 DNA binding at single-cell resolution. This study will first investigate the molecular mechanisms underlying the establishment of aberrant HDAC9 expression, focusing on whether deregulation of the p38MAPK/MEF2C pathway and associated epigenetic changes in HDAC9 promoters are responsible. Next, we will explore how abnormal HDAC9 expression contributes to B-NHL pathogenesis, particularly by modulating the BCL6-p53 feedback loop in favor of BCL6, thereby promoting the loss of p53. Finally, the study aims to develop strategies to target aberrant HDAC9 expression and assess the effectiveness of these interventions by monitoring changes in BCL6 and p53 activity. To achieve these goals, we will employ both in vitro and ex vivo studies, utilizing B-NHL cell lines and primary patient samples. A combination of classical techniques such as bisulfite sequencing, qPCR, confocal microscopy, and flow cytometry, alongside next-generation sequencing (NGS) methods such as RNA-seq, ChIP-seq, and CUT&RUN/Tag, will be applied. Novel technologies, including UV Laser ChIP-seq and Laser Cytometry, will be used to measure site-specific and global DNA binding of crucial transcription factors at both bulk and single-cell levels. These cutting-edge techniques, which have been successfully applied to targets like BCL6, will also be refined and expanded for broader research and clinical diagnostics. The results of this work are anticipated to provide a comprehensive understanding of the role of HDAC9 in B-NHL and to establish a foundation for its targeted therapeutic intervention in clinical settings. Furthermore, by leveraging innovative technology, this study aims to demonstrate proof of principle that monitoring transcription factor binding in single cells can serve as a prognostic marker, paving the way for future clinical applications.

• DFG Programme: Research Grants
• International Connection: Poland
• Cooperation Partner: Dr. Lukasz Szymanski