Year: 2025
Type: article
Abstract: Lymphoma’s epigenetic landscape offers unique insight into disease onset, progression, and treatment outcomes. Somatic mutations in chromatin-modifying genes are a genetic hallmark of the most prevalent types of lymphoma, including Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL). These mutations lead to significant alterations in epigenetic patterns, which help to understand the disease's biology and influence the immune environment within tumors. For instance, the Ezh2 mutation enhances the methylation of H3K27me3 across neighboring genomic regions, suppressing gene expression in Centrocyte B-cells, inducing immune evasion, and greatly altering the tumor microenvironment leading to increased cell proliferation of malignant B-cells. Consequently, there is a significant interest in the development of epigenetic therapies, with one such inhibitor of EZH2 (EZH2i) already approved by the FDA and many others currently in development. Nonetheless, considerable challenges exist in the clinical application of such therapies, including the difficulties in the assessment of their effectiveness due to their slow action. In fact, there's currently no reliable method to verify whether the drugs are hitting their target in lymphoma cells and restoring normal epigenetic patterning. While repeat biopsies have been shown to be useful in assessing the impact of epigenetic therapies, they cannot be performed in more than a tiny handful of patients. Other approaches such as the assessment of epigenetic patterning in peripheral blood cells or skin biopsies cannot reflect the aberrant epigenetic scenario of the actual lymphomas and are known to be inadequate. Therefore, there is an urgent unmet need to devise alternative methods for evaluating the effectiveness of such treatments. Recent advancements in experimental techniques applicable to liquid biopsy enabled the possibility of profiling circulating epigenetic markers providing non-invasive insights into dynamic regulatory changes in the cellular landscape of both healthy and pathological states. By applying cell-free DNA (cfDNA) chromatin immunoprecipitation sequencing (cfChIP-seq assay) to the cohort of lymphoma samples we propose a methodology to access the information about transient epigenetic changes in malignant B-cells that would not be available through sequence analysis alone. We are investigating the feasibility and implications of profiling circulating epigenetic markers in a translational setting, as well as their potential to refine current diagnostic tools and enhance our understanding of mechanisms driving treatment resistance in lymphoma patients. Keywords: bioinformatics; computational and systems biology; liquid biopsy; genomics, epigenomics, and other -omics No potential sources of conflict of interest.
Source: Hematological Oncology
Authors: K. Sienkiewicz, I. Karagiannidis, W. Béguelin, C. E. Mason, A. M. Melnick
Institution: Weill Cornell Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4411321089