Fas is highly expressed on germinal center (GC) B cells, and mutations of FAS have been reported in diffuse large B cell lymphoma (DLBCL). Although GC-derived DLBCL has better overall outcomes than other DLBCL types, some cases are refractory, and the molecular basis for this is often unknown. We show that Fas is a strong cell-intrinsic regulator of GC B cells that promotes cell death in the light zone, likely via T follicular helper (Tfh) cell–derived Fas ligand. In the absence of Fas, GCs were more clonally diverse due to an accumulation of cells that did not demonstrably bind antigen. FAS alterations occurred most commonly in GC-derived DLBCL, were associated with inferior outcomes and an enrichment of Tfh cells, and co-occurred with deficiency in HVEM and PD-L1 that regulate the Tfh–B cell interaction. This work shows that Fas is critically required for GC homeostasis and suggests that loss of Tfh-mediated counterselection in the GC contributes to lethality in GC-derived lymphoma.
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November 25 2020
Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma
Raud Razzaghi,
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Shreya Agarwal,
Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Nikita Kotlov,
Nikita Kotlov
Conceptualization, Investigation, Software
2
BostonGene, Waltham, MA
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Olga Plotnikova,
Olga Plotnikova
Investigation, Software
2
BostonGene, Waltham, MA
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Krystle Nomie,
Krystle Nomie
Writing - original draft
2
BostonGene, Waltham, MA
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Da Wei Huang,
Da Wei Huang
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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George W. Wright,
George W. Wright
Data curation, Formal analysis, Methodology, Writing - review & editing
3
Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Grace A. Smith,
Grace A. Smith
Investigation, Resources
4
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Moyi Li,
Moyi Li
Formal analysis, Investigation
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Katsuyoshi Takata,
Katsuyoshi Takata
Data curation, Investigation, Writing - review & editing
5
Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada
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Maryam Yamadi,
Maryam Yamadi
Data curation, Formal analysis, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Chen Yao,
Chen Yao
Data curation, Software
6
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
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John J. O’Shea,
John J. O’Shea
Funding acquisition, Resources, Visualization, Writing - review & editing
6
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
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James D. Phelan,
James D. Phelan
Conceptualization, Formal analysis, Investigation, Visualization, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Stefania Pittaluga,
Stefania Pittaluga
Investigation, Resources, Visualization
4
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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David W. Scott,
David W. Scott
Data curation, Formal analysis, Investigation, Writing - review & editing
5
Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada
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Jagan R. Muppidi
Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Correspondence to Jagan R. Muppidi: jagan.muppidi@nih.gov
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Raud Razzaghi
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Shreya Agarwal
Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Nikita Kotlov
Conceptualization, Investigation, Software
2
BostonGene, Waltham, MA
Olga Plotnikova
Investigation, Software
2
BostonGene, Waltham, MA
Krystle Nomie
Writing - original draft
2
BostonGene, Waltham, MA
Da Wei Huang
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
George W. Wright
Data curation, Formal analysis, Methodology, Writing - review & editing
3
Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD
Grace A. Smith
Investigation, Resources
4
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Moyi Li
Formal analysis, Investigation
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Katsuyoshi Takata
Data curation, Investigation, Writing - review & editing
5
Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada
Maryam Yamadi
Data curation, Formal analysis, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Chen Yao
Data curation, Software
6
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
John J. O’Shea
Funding acquisition, Resources, Visualization, Writing - review & editing
6
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
James D. Phelan
Conceptualization, Formal analysis, Investigation, Visualization, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Stefania Pittaluga
Investigation, Resources, Visualization
4
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
David W. Scott
Data curation, Formal analysis, Investigation, Writing - review & editing
5
Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada
Jagan R. Muppidi
Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
*
R. Razzaghi and S. Agarwal contributed equally to this paper.
Correspondence to Jagan R. Muppidi: jagan.muppidi@nih.gov
Received:
June 05 2020
Revision Received:
September 01 2020
Accepted:
October 20 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
National Cancer Institute
(NO AWARD)
National Institutes of Health
(NO AWARD)
This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (3): e20201173.
Article history
Received:
June 05 2020
Revision Received:
September 01 2020
Accepted:
October 20 2020
Citation
Raud Razzaghi, Shreya Agarwal, Nikita Kotlov, Olga Plotnikova, Krystle Nomie, Da Wei Huang, George W. Wright, Grace A. Smith, Moyi Li, Katsuyoshi Takata, Maryam Yamadi, Chen Yao, John J. O’Shea, James D. Phelan, Stefania Pittaluga, David W. Scott, Jagan R. Muppidi; Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma. J Exp Med 1 March 2021; 218 (3): e20201173. doi: https://doi.org/10.1084/jem.20201173
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