@article{10.1172/jci.insight.142149, author = {Zuzana Tothova AND Anne-Laure Valton AND Rebecca A. Gorelov AND Mounica Vallurupalli AND John M. Krill-Burger AND Amie Holmes AND Catherine C. Landers AND J. Erika Haydu AND Edyta Malolepsza AND Christina Hartigan AND Melanie Donahue AND Katerina D. Popova AND Sebastian Koochaki AND Sergey V. Venev AND Jeanne Rivera AND Edwin Chen AND Kasper Lage AND Monica Schenone AND Alan D. D’Andrea AND Steven A. Carr AND Elizabeth A. Morgan AND Job Dekker AND Benjamin L. Ebert}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML}, year = {2021}, month = {2}, volume = {6}, url = {https://insight.jci.org/articles/view/142149}, abstract = {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 myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2–mutant (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 poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 (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 was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.}, number = {3}, doi = {10.1172/jci.insight.142149}, url = {https://doi.org/10.1172/jci.insight.142149}, }