NUDT21 Drives T‐Cell Acute Lymphoblastic Leukemia Through Dual Regulation of Alternative Polyadenylation and Transcriptional Activation

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with limited therapeutic options. Here, we identify the alternative polyadenylation (APA) regulator NUDT21 as a key factor in T-ALL maintenance through integrated multi-omics analyses and functional studies. NUDT21 is aberrantly upregulated in T-ALL patients, and its elevated expression is associated with poor clinical outcomes. Mechanistically, NUDT21 exerts dual oncogenic functions. As a core component of the CFIm complex, NUDT21 promotes distal poly(A) site usage of oncogenic transcripts, most prominently UBE2D3, generating long 3'UTR isoforms with enhanced mRNA stability and increased protein expression. Functionally, UBE2D3 acts as a critical downstream effector that sustains leukemia cell proliferation and survival through MYC-dependent signaling. Beyond its canonical role in APA regulation, NUDT21 also localizes to transcriptionally active promoters and interacts with lineage-specific transcription factors, including MYB, RUNX1, and GATA3, to facilitate MYC transcription. Importantly, pharmacological targeting of NUDT21 with ouabain octahydrate induces robust apoptosis in T-ALL cells by promoting NUDT21 protein degradation and concomitant suppression of UBE2D3 and MYC. Collectively, our findings establish NUDT21 as a multimodal oncogenic regulator and a promising therapeutic target in T-ALL.