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

Area of Science:

• Molecular Biology
• Cancer Genetics
• Hematology

Background:

• The cohesin complex is crucial for chromosome stability and gene expression.
• Somatic mutations in cohesin, particularly STAG2, are common drivers in myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

Purpose of the Study:

• To identify genetic vulnerabilities in STAG2-mutant AML.
• To explore therapeutic strategies targeting cohesin-mutant cancers.

Main Methods:

• Genetic dependency screens in STAG2-mutant AML cells.
• Development of a mouse model for STAG2-mutant MDS.
• In vivo and in vitro sensitivity assays to poly(ADP-ribose) polymerase (PARP) inhibitors.
• Analysis of cohesin complex composition and chromatin structure.

Main Results:

• Cohesin-mutant cells exhibit dependencies on DNA damage repair and replication pathways.
• These cells show increased DNA damage and are sensitive to PARP inhibition.
• PARP inhibition selectively depletes cohesin-mutant cells in a preclinical MDS model.
• Cohesin-mutant cells display a shift from STAG2 to STAG1 cohesin complexes, leading to altered DNA loop extrusion and chromatin organization.

Conclusions:

• DNA damage repair and replication are critical dependencies in cohesin-mutant AML.
• PARP inhibition represents a viable therapeutic strategy for cohesin-mutant hematological malignancies.
• Altered cohesin complex composition influences chromatin dynamics and drug sensitivity in these cancers.