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. 2025 Oct 28;9(20):5283-5288.
doi: 10.1182/bloodadvances.2025016897.

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

Waihay J Wong  1   2 , Rebecca L Zon  1   3 , Christopher J Gibson  1 , Caleb Ho  4 , Olga Pozdnyakova  3 , Donna Neuberg  5 , Elisabeth M Battinelli  2 , Marlise R Luskin  1   2 , Zuzana Tothova  1   6 , Elizabeth A Morgan  3 , Benjamin L Ebert  1   6
Affiliations

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

Waihay J Wong et al. Blood Adv. .

Abstract

Myelodysplastic syndrome (MDS) is driven by genetic mutations, but diagnosis relies on morphologic evaluation of bone marrow hematopoiesis. Only a small number of genetic abnormalities define specific bone marrow morphologic features in MDS, such as SF3B1 mutations and deletions of chromosome 5q. We hypothesized that additional genetic alterations are associated with specific dysplastic morphologic features in MDS. We assessed genetic-morphologic associations between commonly mutated genes and 10 morphologic features in a cohort of MDS bone marrows with a high degree of dysplasia. We replicated the association of SF3B1 mutations with ring sideroblasts and found that dysplastic megakaryocytes with separated nuclei were independently associated with STAG2 and/or ASXL1 mutations. In addition, STAG2 mutations were associated with abnormal myeloid nuclear segmentation and myeloid cell hypogranulation. These findings demonstrate that STAG2 and ASXL1 mutations are associated with specific morphologic abnormalities in MDS.

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Conflict of interest statement

Conflict-of-interest disclosure: B.L.E. reports research funding from Novartis and Calico; consulting fees from AbbVie; and is a member of the scientific advisory board for and shareholder in Neomorph Inc, Big Sur Bio, Skyhawk Therapeutics, and Exo Therapeutics. R.L.Z. is a consultant for and stockholder in Triveni Bio. D.N. reports stock ownership in Madrigal Pharmaceuticals. Z.T. reports research funding from Novartis, not related to this work. C.H. is a full-time employee of Foundation Medicine, Inc, which was not involved in this study. The remaining authors declare no competing financial interests.

The current affiliation for W.J.W. is Department of Pathology, Northwestern University, Chicago, IL.

The current affiliation for O.P. is Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.

The current affilation for C.J.G. is Novartis Biomedical Research, Cambridge, MA.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Genetic morphologic associations in MDS. (A) Dysplastic features evaluated include (clockwise from top left) erythroid binucleation, erythroid nuclear irregularity, erythroid karyorrhexis, erythroid mitosis, ring sideroblast, Auer rod, abnormal myeloid nuclear segmentation, myeloid hypogranulation, hypolobated megakaryocyte, and separated megakaryocyte nuclei. (B) Correlation matrix showing association between evaluated dysplastic features and gene mutations in the discovery cohort. Only associations with adjusted P value < .05 are shown. The area of each circle represents the absolute Spearman correlation coefficient (ρ). Mk, megakaryocytes; N, number of samples; N:C, nuclear-to-cytoplasmic.
Figure 2.
Figure 2.
Specific gene mutations are associated with dysplastic features. Forest plots of univariate (open) and multivariable (filled) analyses for gene mutations associated with separated megakaryocyte nuclei (A), abnormal myeloid nuclear segmentation (B), and myeloid hypogranulation (C) in the enrichment cohort. (D-G) Bone marrow biopsy micrographs demonstrate megakaryocytes with widely separated nuclei (arrowheads) in a patient with STAG2, SRSF2, ASXL1, IDH2, KRAS, PTPN11, and subclonal CUX1 and RUNX1 mutations (D) and a patient with germ line GATA2 and secondary somatic STAG2 mutations (E); in contrast, dysplastic megakaryocytes (arrowheads) are present but do not display separated nuclei in a patient with ASXL1, RUNX1, SRSF2, and TET2 mutations (F) or a patient with ASXL1 and SRSF2 mutations (G).
See this image and copyright information in PMC

References

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