TY - JOUR
T1 - Loss of synergistic transcriptional feedback loops drives diverse B-cell cancers
AU - Andrews, Jared M.
AU - Pyfrom, Sarah C.
AU - Schmidt, Jennifer A.
AU - Koues, Olivia I.
AU - Kowalewski, Rodney A.
AU - Grams, Nicholas R.
AU - Sun, Jessica J.
AU - Berman, Leigh R.
AU - Duncavage, Eric
AU - Lee, Yi-Shan
AU - Cashen, Amanda
AU - Oltz, Gene
AU - Payton, Jacqueline E.
N1 - Funding Information:
We thank the Washington University School of Medicine Lymphoma Banking Program of the Division of Medical Oncology in the Department of Medicine for support of the biopsy and banking program; the patients, their caregivers and families, and the patient coordinators who participated in this study. This work was supported by the National Institutes of Health (NIH) grants CA221012 (to J.M.A.) and CA188286 and CA156690 (to E.M.O. and J.E.P.). Additional funding from the Siteman Cancer Center, Barnes-Jewish Hospital Foundation, and the Doris Duke Foundation (to J.E.P.). Sequencing provided by the Genome Technology Access Center, which is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. None of these sources had any role in data collection, analysis, interpretation, trial design, patient recruitment, writing the manuscript, the decision to submit the manuscript, or any other aspect pertinent to the study. None of the authors was paid to write the article by a company or any other agency. The corresponding author (Jacqueline Payton) had full access to all of the data in the study and had final responsibility for the decision to submit for publication.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - B-cell cancer
KW - Epigenetics
KW - Lymphoma
KW - Super-enhancers
KW - Transcriptional regulation and feedback
UR - http://www.scopus.com/inward/record.url?scp=85113612293&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2021.103559
DO - 10.1016/j.ebiom.2021.103559
M3 - Article
C2 - 34461601
AN - SCOPUS:85113612293
SN - 2352-3964
VL - 71
JO - EBioMedicine
JF - EBioMedicine
M1 - 103559
ER -