Genetic alterations of the cohesin complex genes in myeloid malignancies

Abstract

• Recurrent hypomorphic cohesin defects and cohesin low expression were identified in a significant proportion of patients with MDS and AML.• Cohesin mutations likely represent secondary events in clonal hierarchy and contribute to clonal transformation.Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n 5 386), myeloproliferative neoplasms (MPNs) (n 5 55), MDS/MPNs (n 5 169), and AML (n 5 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deepsequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P 5 .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P 5 .017). (Blood.

Epigenetic alterations in acute myeloid leukemias

“…Importantly, these regions are involved in regulating the expression of genes that govern pluripotency/self-renewal in embryonic stem cells. Therefore, it might be that loss-of-function mutations in cohesin lead to transcriptional alteration of genes that have important roles in differentiation and proliferation, eventually leading to clonal evolution and tumorigenesis [98]. In the case of AML, cohesin mutations lead to loss of chromosome interactions between conserved regulatory elements and promoters at specific hematopoietic genes, such as RUNX1: the deregulation of hematopoietic transcription programs could facilitate the development of AML [96].…”

Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome

“…Mutually exclusive loss of function nonsense and frameshift mutations in the cohesin components are found in 11% and 17% of low-and high-risk MDS, respectively. 22,23 Cohesin normally functions to align sister chromatids during mitosis; however, mutations do not result in gross aneuploidy. 7,24 Instead, recent studies have shown that cohesin mutations can promote transformation by driving aberrant transcriptional programs, potentially by disrupting this complex's role in stabilizing DNA loops, such as those involved in enhancer-promoter interactions.…”

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

“…Interestingly, it has been shown that the cohesin complex could functionally interact with Polycomb group proteins to control gene transcription. 46 It is an interesting observation that ASXL gene mutations 47 as well as cohesin gene mutations 48 are enriched in patients with RUNX1-mutated AML. Recently, several experiments have linked cohesin and RUNX1 in hematopoiesis and leukemogenesis.…”