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Aging predisposes B cells to malignancy by activating c-Myc and perturbing the genome and epigenome

View ORCID ProfileAnastasia V. Shindyapina, View ORCID ProfileJosé P. Castro, View ORCID ProfileAlessandro Barbieri, Olga S. Strelkova, João A. Paulo, View ORCID ProfileCsaba Kerepesi, View ORCID ProfileAnna P. Petrashen, View ORCID ProfileMarco Mariotti, Margarita Meer, Yan Hu, Grigoriy Losyev, View ORCID ProfileArtur A. Indzhykulian, View ORCID ProfileSteven P. Gygi, John M. Sedivy, John P. Manis, View ORCID ProfileVadim N. Gladyshev
doi: https://doi.org/10.1101/2021.02.23.432500
Anastasia V. Shindyapina
1Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, USA
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José P. Castro
1Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, USA
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Alessandro Barbieri
2Boston Children’s Hospital, Harvard Medical School, Boston, 02115, USA
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Olga S. Strelkova
3Eaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston 02114 USA
4Department of Otolaryngology – Head and Neck Surgery, Harvard Medical School, Boston, 02114, USA
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João A. Paulo
5Department of Cell Biology, Harvard Medical School, Boston, 02115, USA
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Csaba Kerepesi
1Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, USA
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  • ORCID record for Csaba Kerepesi
Anna P. Petrashen
6Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
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  • ORCID record for Anna P. Petrashen
Marco Mariotti
1Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, USA
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Margarita Meer
1Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, USA
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Yan Hu
1Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, USA
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Grigoriy Losyev
1Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, USA
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Artur A. Indzhykulian
3Eaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston 02114 USA
4Department of Otolaryngology – Head and Neck Surgery, Harvard Medical School, Boston, 02114, USA
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Steven P. Gygi
5Department of Cell Biology, Harvard Medical School, Boston, 02115, USA
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John M. Sedivy
6Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
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John P. Manis
2Boston Children’s Hospital, Harvard Medical School, Boston, 02115, USA
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Vadim N. Gladyshev
1Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, USA
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  • ORCID record for Vadim N. Gladyshev
  • For correspondence: vgladyshev@rics.bwh.harvard.edu
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Abstract

Age is the single major risk factor for human cancer; however, naturally occurring cancers are rarely studied in aged animal models. Laboratory mouse strains spontaneously develop cancer with age and some predominantly die from B-cell lymphoma. Here, we uncover how B-cell lymphoma develops as a consequence of the aging immune system. We found that aged B cells undergo clonal expansions driven by genetic and epigenetic changes and established cell and spleen size as early markers of malignant transformation. High-throughput and omics assays of aged B cells and the use of mouse models revealed that c-Myc is a master regulator of B cell size and clonal expansion. A single-cell RNA-seq analysis suggested that clonal B cells originate from age-associated B cells, memory B cells that accumulate during aging. Further studies showed that c-Myc becomes activated in B cells in response to the aging microenvironment. Thus, c-Myc, aging environment, somatic mutations and the epigenome cooperate to give rise to clonal age-accelerated B cells, which we named Myc+ cells. We further show the relevance of this model to aged human B cells in blood and spleen. This study characterized a first mouse model that captures a natural transition of B cells to a prevalent type of cancer during aging.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 23, 2021.
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Aging predisposes B cells to malignancy by activating c-Myc and perturbing the genome and epigenome
Anastasia V. Shindyapina, José P. Castro, Alessandro Barbieri, Olga S. Strelkova, João A. Paulo, Csaba Kerepesi, Anna P. Petrashen, Marco Mariotti, Margarita Meer, Yan Hu, Grigoriy Losyev, Artur A. Indzhykulian, Steven P. Gygi, John M. Sedivy, John P. Manis, Vadim N. Gladyshev
bioRxiv 2021.02.23.432500; doi: https://doi.org/10.1101/2021.02.23.432500
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Aging predisposes B cells to malignancy by activating c-Myc and perturbing the genome and epigenome
Anastasia V. Shindyapina, José P. Castro, Alessandro Barbieri, Olga S. Strelkova, João A. Paulo, Csaba Kerepesi, Anna P. Petrashen, Marco Mariotti, Margarita Meer, Yan Hu, Grigoriy Losyev, Artur A. Indzhykulian, Steven P. Gygi, John M. Sedivy, John P. Manis, Vadim N. Gladyshev
bioRxiv 2021.02.23.432500; doi: https://doi.org/10.1101/2021.02.23.432500

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