ResearchIn-Press PreviewHematologyOncology
Open Access | 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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Vallurupalli, M.
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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
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Schenone, M.
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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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Published December 22, 2020 - More info
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.