Cohesin mutations in myeloid malignancies made simple

Abstract

Purpose of review: Recurrent loss of function mutations within genes of the cohesin complex have been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). STAG2 is the most commonly mutated cohesin member in AML as well as solid tumors. STAG2 is recurrently, mutated in Ewing's Sarcoma, bladder cancer, and glioblastoma, and is one of only ten genes known to be recurrently mutated in over four distinct tissue types of human cancer RECENT FINDINGS: The cohesin complex, a multiprotein ring, is canonically known to align and stabilize replicated chromosomes prior to cell division. Although initially thought to lead to unequal chromosomal separation in dividing cells, data in myeloid malignancies show this is not observed in cohesin mutant MDS/AML, either in large patient cohorts or mouse models. Mounting evidence supports a potential alternate mechanism whereby drivers of cell-type specific gene expression and hematopoietic development are impaired through alteration in three-dimensional nuclear organization and gene structure.

Summary: Understanding the functional consequences of cohesin mutations in regulating lineage-specific and signal-dependent defects and in myeloid transformation will identify novel pathophysiologic mechanisms of disease and inform the development of novel therapeutic targets.

FIGURE 1.

Proposed mechanism for tumor-suppressor function of cohesin in cancer. Complex chromatin structure at stem-maintenance genes either have increased affinity for remaining cohesin or have redundant structural stability and maintain expression. Genes essential for lineage priming, differentiation, and environmental response are highly sensitive and expression is impaired. Abnormal HSC maturation likely contributes to a myelodysplasia phenotype and with cooperating mutations leading to an overall relaxed chromatin state, which can amplify the signal of an oncogene-addicted clone resulting in clonal expansion and transformation.