Myelodysplastic syndromes are clonal bone marrow failure disorders demonstrating variable degrees of cytopenias, morphologic dysplasia, and risk of progression to acute myeloid leukemia.

We hypothesized that MDS with a normal karyotype (NK) would exhibit a unique mutational or morphologic signature.

We investigated the morphologic features and genetic profiles of 89 patients with myelodysplastic syndrome (MDS), including 42 with a NK and 47 with an abnormal karyotype (non-NK). We used next-generation sequencing (NGS) to detect pathogenic variants and performed morphologic review by two independent hematopathologists in a blinded manner with a nested set of 43 control cases.

NK and non-NK cases showed similar levels of dysplasia in granulocytes and erythroids, but non-NK cases showed significantly more dysplasia in megakaryocytes (P = 0.037). The mutational burden was similar between NK and non-NK cases. TET2 and SF3B1 mutations were more frequent in NK cases (P = 0.029 and P = 0.013, respectively), and TP53 mutations were more frequent in non-NK cases (P = 0.007). Overall, higher mutational burden was associated with higher levels of megakaryocyte dysplasia (P = 0.003), but there was no association with granulocytic or erythroid dysplasia. Cases with STAG2 mutations were associated with higher overall megakaryocyte dysplasia (P = 0.0016) and proportion of megakaryocytes with separate nuclear lobes (P < 0.0001).

The megakaryocyte lineage is the most expressive in terms of reflecting morphologic dysplasia due to cytogenetic or molecular abnormalities. MDS with NK shows similar morphologic features to non-NK cases, but our findings suggest that non-NK cases exhibit higher levels of megakaryocytic dysplasia.