NUDT21 knockdown modulates alternative polyadenylation and promotes leukemic transformation in myelodysplastic syndromes

Progression of myelodysplastic neoplasms (MDS) to secondary acute myeloid leukemia (sAML) involves complex clonal evolution; however, the role of alternative polyadenylation (APA) regulators such as NUDT21 remains unclear. This study aimed to investigate the effects of NUDT21 knockdown on gene expression profiles in MDS cells and their correlation with clinicopathological features in MDS. NUDT21 was knocked down via shRNA in MDS cell lines (SKM-1, MUTZ-1), followed by transcriptome sequencing, functional assays, and clinical validation in 40 MDS patients. Rescue experiments were performed by overexpressing DDX60 in NUDT21 knockdown cells and treating cells with the STAT3 inhibitor Stattic to validate the downstream mechanism. Data showed that knockdown of NUDT21 altered the expression of multiple downstream genes and related pathways. The expressions of DDX60, SRPK3, and XAF1 were positively correlated with the expression of NUDT21. NUDT21 overexpression was associated with the increased sAML transformation rate in MDS patients. NUDT21 was associated with the transformation of MDS into sAML, potentially by increasing the expression level of DDX60 and activating the JAK2/STAT3 pathway. Rescue experiments confirmed that DDX60 overexpression restored JAK2/STAT3 phosphorylation and reversed the phenotypic changes induced by NUDT21 knockdown, while STAT3 inhibition abrogated these effects, further supporting the role of the DDX60-JAK2/STAT3 axis in NUDT21-mediated MDS progression. In conclusion, NUDT21 appears to be associated with disease progression and leukemic transformation in MDS.