NUDT21 Promotes Myelodysplastic Syndrome Progression by Regulating SRSF2 Expression via Alternative Polyadenylation.
Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm with a high risk of leukemic transformation. Alternative polyadenylation (APA) is an important post-transcriptional mechanism, and its dysregulation is closely linked to the pathogenesis of hematological malignancies. This study aimed to clarify the regulatory role of the NUDT21-APA-SRSF2 axis in the progression of myelodysplastic syndrome (MDS). To this end, we established MDS cell models overexpressing or knocking down NUDT21 and SRSF2. The regulatory mechanism and functional impacts of this axis were systematically evaluated using RT-qPCR, Western blot, CCK-8 assay and flow cytometry; APA site analysis mediated by specific primers and transcriptome sequencing. The results showed that the expression of NUDT21 was negatively correlated with that of SRSF2 (p < 0.05). Overexpression of NUDT21 promoted the utilisation of distal polyadenylation sites on SRSF2, increasing the expression of its long 3'UTR variants; conversely, NUDT21 knockdown produced the opposite effect (p < 0.05). Functionally, NUDT21 enhanced MDS cell proliferation and inhibited apoptosis, though this effect was reversed by co-overexpression of SRSF2. Furthermore, SRSF2 could antagonize the regulatory effect of NUDT21 on the cell cycle. In summary, our in vitro data demonstrate that NUDT21 remodels SRSF2 isoform balance via alternative polyadenylation (APA) and regulates biological functions of MDS-derived cells. The NUDT21-APA-SRSF2 axis represents a key regulatory cascade with potential therapeutic implications.