Reduced STAG2 expression in myelodysplastic neoplasms and acute myeloid leukemia myelodysplasia-related: a potential biomarker associated with aneuploidy and disease progression

Background Myelodysplastic neoplasms (MDS) are a clonal hematopoietic stem cell disease with an increased risk of progression to acute myeloid leukemia (AML). Cytogenetic abnormalities, mainly aneuploidies, occur in 40%–60% of cases and are critical for MDS diagnosis and prognosis. Nevertheless, the MDS heterogeneity highlights the ongoing need for additional studies regarding mechanisms driving its development and progression, contributing to the identification of biomarkers. In this context, STAG2 , a key component of the cohesin complex, has been implicated in the pathogenesis of MDS. However, the expression of the STAG2 protein and its role in MDS biology remain unexplored. Thus, this study aimed to analyze the STAG2 protein expression profile in MDS patients, its association with karyotypes, evolution to AML, and its potential as a prognosis biomarker. Methods STAG2 expression was analyzed by immunohistochemistry in bone marrow biopsies from 97 MDS patients (24 pediatric, 73 adult) and 20 controls (10 pediatric, 10 adult). Cytogenetic analysis was performed by G-banding and fluorescence in situ hybridization (FISH). Protein–protein interaction (PPI) networks were conducted using the STRING database, and functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Transcription factors PPIs (TFPPI) databases. Results Reduced STAG2 expression was detected in 67% (65/97) of MDS cases, with 51.5% exhibiting intermediate and 15% low expression. Abnormal karyotypes were found in 41% (40/97) of patients, among them STAG2 reduction was present in 65% (13/20) with structural alterations, 69% (9/13) with aneuploidies, and 86% (6/7) with both. Reduced STAG2 expression was particularly associated with complex karyotypes (86%) and trisomy of chromosome 8 (83%). Bioinformatic analysis showed that STAG2 interactors were enriched in pathways related to mitotic regulation, chromatin and epigenetic control, and 3D genome organization. Conclusion Our findings suggest that reduced STAG2 protein expression plays a relevant role in MDS pathogenesis. Immunohistochemical assessment of STAG2 may be incorporated into the clinical workflows as a potential diagnostic and prognostic biomarker, as well as indicate therapeutic targets, particularly in association with complex karyotypes and trisomy 8.