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

JCI Insight. 2021 Feb 8;6(3):e142149. doi: 10.1172/jci.insight.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.

Keywords: Epigenetics; Hematology; Leukemias; Mouse models; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA Damage
  • DNA Repair / genetics*
  • Disease Models, Animal
  • Female
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Mutant Strains
  • Mice, SCID
  • Mice, Transgenic
  • Mutation*
  • Myelodysplastic Syndromes / drug therapy
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / metabolism*
  • Nuclear Proteins / genetics
  • Phthalazines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • U937 Cells
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Nuclear Proteins
  • Phthalazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • STAG1 protein, human
  • STAG2 protein, human
  • cohesins
  • talazoparib