Cohesin Mutations in Myeloid Malignancies

Abstract

Acute Myeloid Leukemia (AML) is a hematologic malignancy with a poor prognosis. Recent genome-wide sequencing studies have identified frequent mutations in genes encoding members of the cohesin complex. Mutations in cohesin contribute to myeloid malignancies by conferring enhanced self-renewal of hematopoietic stem and progenitor cells but the mechanisms behind this phenotype have not been fully elucidated. Of note, cohesin mutations are highly prevalent in acute megakaryocytic leukemia associated with Down syndrome (DS-AMKL), where they occur in over half of patients. Evidence suggests that cohesin mutations alter gene expression through changes in chromatin accessibility and/or aberrant targeting of epigenetic complexes. In this review we discuss the pathogenic mechanisms by which cohesin mutations contribute to myeloid malignancies.

Figure 1, Key Figure. Cohesin mutations contribute to acute myeloid leukemia

Wild-type cohesin mediates gene promoter-enhancer interactions to maintain proper gene expression. Cohesin mutations disrupt cohesin ring assembly which results in impaired differentiation and enhanced self-renewal of HSPCs. Recent research shows that disruption of cohesin in hematopoietic cells results in alterations in chromatin accessibility and/or disrupted targeting of epigenetic regulators such as the PRC2 complex, and drives a stem cell gene expression program. In the presence of additional oncogenic mutations, such as FLT3-ITD, cohesin haploinsufficiency leads to leukemia.

Figure I. Cohesin structure and functions

A) The core cohesin subunits SMC3, SMC1A, RAD21, and either STAG1 or STAG2 form the core subunits to generate a cohesin “ring”. In myeloid malignancies, all four core subunits are recurrently mutated with the exception of STAG1. Red circles and blue circles represent the hinge and ATPase head domains respectively of the SMC1 and SMC3 proteins. B) The canonical function of the cohesin complex is during mitosis where it maintains sister chromatin cohesion. C) Cohesin stabilizes DNA loops during interphase, facilitating interactions. Through a direct interaction with CTCF, higher order chromatin structures are stabilized, organizing the genome into topologically associated domains and sub-megabase topologically associated domains. D) Cohesin permits distal cis-regulatory elements such as enhancers to interact with genes and regulate gene expression. CTCF and cohesin co-regulate DNA looping; CTCF can mediate DNA loops independent of cohesin, and vice-versa.