m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis
(2023) In Molecular Cell 83(7). p.11-1179- Abstract
- 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 m6A demethylation fine-tunes SF3B1 translation directing splicing of central DNA repair and epigenetic... (More)
- 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 m6A 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/17ff5a26-a0f8-4a59-b96b-61d43eeee065
- author
- Ciesla, Maciej LU ; Cao Thi Ngoc, Phuong LU ; Muthukumar, Sowndarya LU ; Todisco, Gabriele ; Madej, Magdalena LU ; Fritz, Helena LU ; Dimitriou, Marios ; Incarnato, Danny ; Hellström-Lindberg, Eva and Bellodi, Cristian LU
- organization
- publishing date
- 2023-03-20
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Molecular Cell
- volume
- 83
- issue
- 7
- pages
- 11 - 1179
- publisher
- Cell Press
- external identifiers
-
- scopus:85151282694
- pmid:36944332
- ISSN
- 1097-2765
- DOI
- 10.1016/j.molcel.2023.02.024
- language
- English
- LU publication?
- yes
- id
- 17ff5a26-a0f8-4a59-b96b-61d43eeee065
- date added to LUP
- 2023-04-06 09:40:03
- date last changed
- 2024-02-19 12:25:35
@article{17ff5a26-a0f8-4a59-b96b-61d43eeee065, abstract = {{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 m6A 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.}}, author = {{Ciesla, Maciej and Cao Thi Ngoc, Phuong and Muthukumar, Sowndarya and Todisco, Gabriele and Madej, Magdalena and Fritz, Helena and Dimitriou, Marios and Incarnato, Danny and Hellström-Lindberg, Eva and Bellodi, Cristian}}, issn = {{1097-2765}}, language = {{eng}}, month = {{03}}, number = {{7}}, pages = {{11--1179}}, publisher = {{Cell Press}}, series = {{Molecular Cell}}, title = {{m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis}}, url = {{http://dx.doi.org/10.1016/j.molcel.2023.02.024}}, doi = {{10.1016/j.molcel.2023.02.024}}, volume = {{83}}, year = {{2023}}, }