m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis.

Maciej Cieśla*, Phuong Cao Thi Ngoc, Sowndarya Muthukumar, Gabriele Todisco, Magdalena Madej, Helena Fritz, Marios Dimitriou, Danny Incarnato, Eva Hellström-Lindberg, Cristian Bellodi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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SF3B1 is the most mutated splicing factor (SF) in myelodysplastic syndromes (MDSs), which are clonal hematopoietic disorders with variable risk of leukemic transformation. Although tumorigenic SF3B1 mutations have been extensively characterized, the role of "non-mutated" wild-type SF3B1 in cancer remains largely unresolved. Here, we identify a conserved epitranscriptomic program that steers SF3B1 levels to counteract leukemogenesis. Our analysis of human and murine pre-leukemic MDS cells reveals dynamic regulation of SF3B1 protein abundance, which affects MDS-to-leukemia progression in vivo. Mechanistically, ALKBH5-driven 5' UTR m 6A demethylation fine-tunes SF3B1 translation directing splicing of central DNA repair and epigenetic regulators during transformation. This impacts genome stability and leukemia progression in vivo, supporting an integrative analysis in humans that SF3B1 molecular signatures may predict mutational variability and poor prognosis. These findings highlight a post-transcriptional gene expression nexus that unveils unanticipated SF3B1-dependent cancer vulnerabilities.

Original languageEnglish
Pages (from-to)1165-1179
Number of pages15
JournalMolecular Cell
Early online date8-Mar-2023
Publication statusPublished - Apr-2023

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