STAG2 – Acute Myeloid Leukemia

STAG2, encoding a core component of the cohesin complex, is recurrently mutated in acute myeloid leukemia (AML), with loss-of-function and missense variants reported across multiple large cohorts. In a study of 389 uniformly treated AML patients, 5 harbored somatic STAG2 mutations (1.3%) (PMID:24335498). A multicenter analysis of 1,615 intensively treated AML cases further demonstrated that STAG2 mutations co-occur with normal karyotype and adverse co-mutational patterns, defining a distinct clinical subset (PMID:36693840).

Genetic evidence supports a somatic, non-familial mode of disease association. Case series in a South Asian population identified a recurrent missense variant c.1576C>T (p.Leu526Phe) in three unrelated AML patients, underscoring population-specific alleles (PMID:32655615). Across studies, STAG2 variant spectrum includes nonsense, frameshift, splice site, and missense changes, consistent with a loss-of-function mechanism.

Functional assays reveal that STAG2 truncating mutations frequently impair sister chromatid cohesion and reduce interaction with regulatory subunits such as WAPL, PDS5A, and PDS5B, whereas some tumor-derived missense alleles retain canonical cohesion function (PMID:26871722). In cohesin-mutant AML models, STAG2 deficiency increases DNA damage and sensitizes cells to PARP inhibition, establishing therapeutic vulnerabilities (PMID:33351783). Genome-wide CRISPR dependency screens identified synthetic lethality between STAG2 loss and its paralog STAG1, highlighting strategies for targeted therapy (PMID:32467316).

While several studies correlate STAG2 mutations with poor prognosis and altered clinical features, multivariable analyses in large cohorts have yielded conflicting results regarding independent prognostic impact on remission rates and survival (PMID:36693840).

In summary, STAG2 somatic mutations occur recurrently in AML, contribute to leukemogenesis via cohesin dysfunction, and confer distinct clinical and therapeutic implications. Screening for STAG2 variants in AML patients can refine risk stratification and guide precision therapies exploiting DNA repair deficiencies and cohesin synthetic lethality.

Key Take-home: STAG2 mutations define a molecularly distinct and therapeutically actionable AML subset.

References

• Blood • 2014 • Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. PMID:24335498
• Blood Cancer Journal • 2023 • Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome. PMID:36693840
• Frontiers in Genetics • 2020 • Novel Genetic Variations in Acute Myeloid Leukemia in Pakistani Population. PMID:32655615
• PLoS Genetics • 2016 • Intact Cohesion, Anaphase, and Chromosome Segregation in Human Cells Harboring Tumor-Derived Mutations in STAG2. PMID:26871722
• JCI Insight • 2021 • Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML. PMID:33351783
• Life Science Alliance • 2020 • STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers. PMID:32467316

Evidence Based Scoring (AI generated)