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.
Highlights
The cohesin complex is a multimeric protein complex that forms a ring structure around DNA molecules and plays multiple key roles in spatial organization of eukaryotic genomes
To study the cellular consequences of cohesin mutations in myeloid malignancies, we used CRISPR/Cas9 to engineer a spectrum of predicted LOF stromal antigen 2 (STAG2), SMC3, and RAD21 mutations identified in patients in acute myeloid leukemia (AML) cell lines WT for all cohesin subunits and modulators
Since both STAG1- and STAG2-containing cohesin complexes participate in sister chromatid cohesion, we examined whether loss of STAG1 in STAG2-deficient cells would lead to aberrant sister chromatid cohesion
Summary
The cohesin complex is a multimeric protein complex that forms a ring structure around DNA molecules and plays multiple key roles in spatial organization of eukaryotic genomes. Cohesin proteins are involved in several essential cellular functions, including sister chromatid cohesion, chromatin loop organization, transcriptional activation, and DNA replication and damage repair, among others Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal diseases of mutated hematopoietic stem and progenitor cells (HSPCs) characterized by abnormal differentiation and proliferation caused by somatic mutations in genes encoding transcription factors, epigenetic regulators, chromatin modifiers, and splicing factors [4, 5]. Targeted inactivation of Smc or Stag, and overexpression of mutant cohesin genes in WT mouse and human HSPCs, have been previously studied [12,13,14,15], but no cohesin-mutant models currently exist that recapitulate the natural evolution of cohesinmutant myeloid disease in the context of clonal hematopoiesis
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