Year: 2021
Type: article
Study design: Observational Study
Abstract: Background The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping "cell-of-origin". Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry. Methods We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays). Findings From the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR . More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2 ( POU2F2 ), and RUNX3 . Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation. Interpretation Our study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma. Funding National Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation.
Source: EBioMedicine
Institution: Washington University in St. Louis
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,500
Awards: Defining the Transcriptional Regulation and Genomic Organization of FAIM3 and PIGR, Human Ig Receptors Involved in Immunity, Auto-Immune Disease, and Lymphoma, TARGETING EPIGENOMIC SIGNATURES IN NON-HODGKIN LYMPHOMA FOR NOVEL THERAPEUTICS, Washington University Institute of Clinical and Translational Sciences, SEQUENCE-SPECIFIC CHROMATIN MODIFIERS; NOVEL PROTEIN THERAPEUTICS FOR B CELL LYMPHOMA, Washington University Institute of Clinical and Translational Sciences, Cancer Center Support Grant
OpenAlex ID: W3195876029