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

abstractMyelodysplastic 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.