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.
Zuzana Tothova, Anne-Laure Valton, Rebecca A. Gorelov, Mounica Vallurupalli, John M. Krill-Burger, Amie Holmes, Catherine C. Landers, J. Erika Haydu, Edyta Malolepsza, Christina Hartigan, Melanie Donahue, Katerina D. Popova, Sebastian Koochaki, Sergey V. Venev, Jeanne Rivera, Edwin Chen, Kasper Lage, Monica Schenone, Alan D. D’Andrea, Steven A. Carr, Elizabeth A. Morgan, Job Dekker, Benjamin L. Ebert
Usage data is cumulative from September 2022 through September 2023.
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.