Loss of Synergistic Transcriptional Feedback Loops Drives Diverse B-Cell Cancers

Background: The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping “cell-of-origin”. Dynamic changes to the epigenome are essential regulators of differentiation. Therefore, we reasoned that these cancers may be driven by shared mechanisms disruption in transcriptional circuitry. Methods: We compared purified malignant B-cells from 52 patients with normal subsets (germinal center centrocytes centroblasts, naive memory B-cells) 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, genome copy number (microarrays). Findings: From resulting data, identified gains active enhancers/super-enhancers likely promote unchecked receptor signaling, including one validated near immunoglobulin superfamily receptors FCMR PIGR. More striking pervasive was profound loss key identity TFs, tumor suppressors their super-enhancers, EBF1, OCT2(POU2F2), RUNX3. Using a novel approach identify feedback, showed core circuitries self-regulating. Their selective gain form complex, iterative, interactive process curbs maturation spurs proliferation. Interpretation: Our study is first map circuitry blood cancers. demonstrate critical subset TFs cognate enhancers self-regulatory feedback loops whose mechanism underlying diverse subtypes lymphoma. Funding: National Institute Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation. Declaration Interest: None declare. Ethical Approval: De-identified peripheral blood, lymph node biopsies, excised were obtained FL, DLBCL, or CLL healthy tonsillectomy (Table 1 Fig. S1A) seen at Washington University School Medicine who provided informed consent under IRB-approved protocols concordance Declaration Helsinki. Due yield constraints, some samples not subjected all assays.