Cohesin mutations in myeloid malignancies

Abstract

Cohesin is a multisubunit protein complex that forms a ring-like structure around DNA. It is essential for sister chromatid cohesion, chromatin organization, transcriptional regulation, and DNA damage repair and plays a major role in dynamically shaping the genome architecture and maintaining DNA integrity. The core complex subunits STAG2, RAD21, SMC1, and SMC3, as well as its modulators PDS5A/B, WAPL, and NIPBL, have been found to be recurrently mutated in hematologic and solid malignancies. These mutations are found across the full spectrum of myeloid neoplasia, including pediatric Down syndrome-associated acute megakaryoblastic leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and de novo and secondary acute myeloid leukemias. The mechanisms by which cohesin mutations act as drivers of clonal expansion and disease progression are still poorly understood. Recent studies have described the impact of cohesin alterations on self-renewal and differentiation of hematopoietic stem and progenitor cells, which are associated with changes in chromatin and epigenetic state directing lineage commitment, as well as genomic integrity. Herein, we review the role of the cohesin complex in healthy and malignant hematopoiesis. We discuss clinical implications of cohesin mutations in myeloid malignancies and discuss opportunities for therapeutic targeting.

Graphical abstract

Figure 1.

Cohesin complex mutations in myeloid malignancies. The core members of the cohesin complex ring and its loader complex (A) and the frequency of mutations (B) according to diagnostic subgroup: de novo AML (n = 2170); NPM1-mutant AML (n = 418); FLT3-ITD-mutant AML (n = 341); t(8;21) AML (n = 254); inv(16) AML (n = 189); MDS (n = 1596); sAML (n = 93); AML-MRC (n = 106); CMML (n = 224); pediatric MDS (n = 38); pediatric AML (n = 993); and DS-AMKL (n = 190). Mutation frequency was calculated as frequency of positive reported cases within the total tested cohort in a single study or averaged across multiple available cohorts. AML-MRC, AML with myelodysplasia-related changes; CMML, chronic myelomonocytic leukemia; DS-AMKL, Down syndrome–associated acute megakaryoblastic leukemia.

Figure 2.

Sister chromatid cohesion–dependent functions of the cohesin complex. (A) Cohesin stabilizes replication forks during DNA replication and restarts stalled replication forks. (B) Cohesin is actively recruited to sites of DNA double-strand breaks to bring the damaged sister chromatid in close proximity of its nondamaged sister chromatid to be used as a donor template during the process of homologous recombination-mediated repair.

Figure 3.

Sister chromatid cohesion–independent functions of the cohesin complex. (A) Cohesin mutations lead to increased intermixing of transcriptionally active A compartments and transcriptionally inactive B compartments. (B) Cohesin-mutant cells preserve TAD boundaries, albeit with weaker insulation, extrude longer loops and lose a subset of shorter E-P loops, which drives transcriptional changes. STAG1-cohesin is recruited to maintain chromatin organization in STAG2-mutant cells. (C) Cohesin is recruited along with the PRC complex to mediate epigenetic silencing of the HOX gene cluster at the level of nucleosomes.