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

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 (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)
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author
; ; ; ; ; ; ; ; and
organization
publishing date
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}},
}