Somatic mutations in STAG2 are associated with separated megakaryocyte nuclear lobes in myelodysplastic syndromes

Authors

Wong WJ

Zon RL

Gibson CJ

Ho C

Pozdnyakova O

Neuberg D

Battinelli EM

Luskin MR

Tothova Z

Morgan EA

Ebert BL

Doi

10.1182/bloodadvances.2025016897

PMID: 21909114 · DOI: 10.1182/bloodadvances.2025016897 · Journal: Blood Advances (2025)

TL;DR

In two independent MDS cohorts (discovery n=80, enrichment n=155), the authors systematically correlated somatic mutations in commonly mutated myeloid genes with 10 bone marrow dysplastic features. They found that STAG2 and ASXL1 mutations are independently associated with separated megakaryocyte nuclei, and STAG2 mutations are additionally associated with abnormal myeloid nuclear segmentation and myeloid cell hypogranulation.

Cohort & data

  • Discovery cohort: 80 MDS bone marrows (from 272 screened) with prominent dysplasia, diagnosed at Brigham and Women’s Hospital 2013-2014; sequenced with a 50-gene targeted panel (VAF cutoff 2%).
  • Enrichment cohort: 155 myeloid neoplasms with myelodysplastic features (from 1047 screened), diagnosed 2014-2018; sequenced with a 95-gene clinical panel.
  • Enrichment cohort was selected to represent all combinations of mutations in STAG2, RUNX1, SRSF2, ASXL1, and SETBP1.
  • Cancer type: MDS.
  • Method: targeted-dna-seq (50-gene and 95-gene panels).

Key findings

  • Separated megakaryocyte nuclei and STAG2: Discovery cohort multivariable OR 32.4 (95% CI 5.45-624.0; P=0.001); enrichment cohort multivariable OR 5.54 (95% CI 2.62-12.1; P<0.001).
  • Separated megakaryocyte nuclei and ASXL1: Enrichment cohort multivariable OR 2.55 (95% CI 1.19-5.67; P=0.018).
  • Abnormal myeloid nuclear segmentation and STAG2: Enrichment cohort multivariable OR 3.04 (95% CI 1.23-7.65; P=0.016).
  • Myeloid cell hypogranulation and STAG2: Enrichment cohort multivariable OR 6.48 (95% CI 2.63-16.7; P<0.001).
  • SRSF2 association with separated megakaryocyte nuclei in the discovery cohort was likely confounded by co-mutation with STAG2 and was not confirmed in the enrichment analysis.
  • SF3B1 and TP53 mutations were associated with erythroid dysplasia, consistent with known roles in erythropoiesis.
  • SETBP1 mutations were independently associated with abnormal granulocytic nuclear segmentation in the discovery cohort (OR 12.2; 95% CI 1.29-267.4; P=0.042).

Genes & alterations

  • STAG2 — somatic loss-of-function mutations; strongest association with separated megakaryocyte nuclei (69% mutated vs 22% unmutated; P<0.0001), abnormal myeloid nuclear segmentation (58% vs 19%; P<0.0001), and hypogranulation (74% vs 21%; P<0.0001).
  • ASXL1 — somatic mutations; independently associated with separated megakaryocyte nuclei (47% mutated vs 24% unmutated; P=0.0002).
  • SRSF2 — mutations associated with megakaryocyte dysplasia in discovery cohort but confounded by STAG2 co-mutation.
  • RUNX1 — mutations associated with megakaryocytic dysplasia in univariate analysis; protective against nuclear segmentation abnormality in enrichment multivariable analysis.
  • SETBP1 — mutations associated with abnormal granulocytic nuclear segmentation.
  • SF3B1 — replicated association with ring sideroblasts.
  • TP53 — associated with erythroid dysplasia.
  • NRAS — univariate association with abnormal myeloid nuclear segmentation (OR 10.4; P=0.045).

Clinical implications

  • Presence of separated megakaryocyte nuclei on bone marrow biopsy may serve as a morphologic indicator of underlying STAG2 or ASXL1 mutations in MDS, analogous to ring sideroblasts for SF3B1.
  • Integration of morphologic features with mutational profiling could refine MDS subtyping and diagnosis.
  • No direct therapeutic implications were demonstrated in this study.

Limitations & open questions

  • The discovery cohort was enriched for prominent dysplasia, limiting generalizability to all MDS patients.
  • Co-occurrence of mutations confounds individual gene-morphology associations despite enrichment cohort design.
  • Precise mechanistic link between STAG2 (cohesin complex) loss and megakaryocyte nuclear separation remains unclear.
  • Study did not assess clinical outcomes (survival, treatment response) in relation to these genotype-morphology associations.
  • VAF thresholds for morphologic prediction were derived from relatively small sample sizes; replication in larger cohorts needed.

Citations from this paper used in the wiki

  • “the presence of separated megakaryocyte nuclei in MDS is strongly associated with mutations in STAG2 (69% of mutated vs 22% of unmutated; P < .0001) and ASXL1 (47% of mutated vs 24% of unmutated; P = .0002)” — Discussion.
  • “STAG2 mutations in MDS are significantly associated with abnormal myeloid nuclear segmentation (58% vs 19%; P < .0001) and myeloid cell hypogranulation (74% vs 21%; P < .0001)” — Discussion.
  • “inactivation of cohesin-mediated loop extrusion in myeloid cells results in nuclear hyper-segmentation and neutrophil differentiation, suggesting a potential mechanism for STAG2 and other cohesin components in regulating nuclear segmentation and shape” — Discussion.

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