Study on the mechanism of action of NUDT21 in acute T-lymphocytic leukemia [PAS-seq]

Alternative polyadenylation (APA) is a widespread post-transcriptional mechanism that regulates transcript stability, localization, and translation. While dysregulated APA has been implicated in multiple cancers, its role in T-cell acute lymphoblastic leukemia (T-ALL) remains poorly understood. Here, we identify NUDT21, a core subunit of the APA machinery, as an essential oncogenic regulator in T-ALL. NUDT21 is significantly upregulated in T-ALL patient samples and associated with poor prognosis. Functional assays demonstrate that NUDT21 knockdown inhibits T-ALL cell proliferation, induces apoptosis, and suppresses leukemia progression in vivo. Integrative PAS-seq and RNA-seq analysis reveals that NUDT21 maintains distal polyadenylation site usage of oncogenic transcripts, including UBE2D3, whose 3′UTR shortening upon NUDT21 loss leads to decreased expression and impaired leukemic cell growth. In addition to its APA role, NUDT21 occupies gene regulatory regions and directly activates transcriptional programs enriched for MYC and E2F targets, promoting cell cycle progression and ribosome biogenesis. Pharmacological suppression of NUDT21 using ouabain, a cardiac glycoside, downregulates UBE2D3 and E2F/MYC effectors, resulting in robust anti-leukemic effects.Our findings reveal a dual regulatory role of NUDT21 in T-ALL, functioning through both APA-dependent and APA-independent mechanisms to sustain leukemic proliferation. Targeting NUDT21 or its downstream programs represents a promising therapeutic strategy for T-ALL.