4.7 Article

Loss of synergistic transcriptional feedback loops drives diverse B-cell cancers

Journal

EBIOMEDICINE
Volume 71, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.ebiom.2021.103559

Keywords

B-cell cancer; Lymphoma; Transcriptional regulation and feedback; Epigenetics; Super-enhancers

Funding

  1. National Institutes of Health (NIH) [CA221012, CA188286, CA156690]
  2. Siteman Cancer Center, Barnes-Jewish Hospital Foundation
  3. Doris Duke Foundation
  4. Genome Technology Access Center
  5. NCI Cancer Center Support Grant [P30 CA91842]
  6. National Center for Research Resources (NCRR), a component of the NIH [UL1 TR000448]

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This study mapped the transcriptional circuitry of the most common blood cancers, revealing that a critical subset of B-cell transcription factors and their cognate enhancers form self-regulatory transcriptional feedback loops, representing a shared mechanism underlying diverse subtypes of B-cell lymphoma.
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, naive and memory B-cells) from 36 donor tonsils using >325 high -reso-lution 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 iden-tity 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 tran-scriptional 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. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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