Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

Zuzana Tothova; Anne-Laure Valton; Rebecca Gorelov; Mounica Vallurupalli; John M. Krill-Burger; Amie Holmes; Catherine C. Landers; J. Erika Haydu; Edyta Malolepsza; Christina R. Hartigan; Melanie Donahue; Katerina D. Popova; Sebastian H. J. Koochaki; Sergey V. Venev; Jeanne F. Rivera; Edwin Chen; Kasper Lage; Monica Schenone; Alan D. D'Andrea; Steven A. Carr; Elizabeth A. Morgan; Job Dekker; Benjamin L. Ebert

doi:10.1172/jci.insight.142149

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

Find articles by Rivera, J. in: JCI | PubMed | Google Scholar

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

Find articles by Chen, E. in: JCI | PubMed | Google Scholar

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

Find articles by Lage, K. in: JCI | PubMed | Google Scholar

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

Find articles by Schenone, M. in: JCI | PubMed | Google Scholar |

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

Find articles by D'Andrea, A. in: JCI | PubMed | Google Scholar

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

Find articles by Carr, S. in: JCI | PubMed | Google Scholar |

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

Find articles by Morgan, E. in: JCI | PubMed | Google Scholar

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, United States of America

³Cancer Program, Broad Institute, Cambridge, United States of America

⁴Department of Radiation Oncology, Dana-Farber Cancder Institute, Boston, United States of America

⁵Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

⁶Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America

⁷Department of Pathology, Brigham and Women's Hospital, Boston, United States of America

Find articles by Ebert, B. in: JCI | PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.142149.
Copyright © 2020, Tothova et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published December 22, 2020 - Version history

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer including myelodysplatic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of STAG2-mutant AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to PARP inhibition. We developed a mouse model of MDS in which Stag2 mutations arise as clonal secondary lesions in the background of clonal hematopoiesis driven by Tet2 mutations, and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which is associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and RPA proteins. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

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Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

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