2. Academic Validation
  3. m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis

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

  • Mol Cell. 2023 Apr 6;83(7):1165-1179.e11. doi: 10.1016/j.molcel.2023.02.024.
Maciej Cieśla 1,  Phuong Cao Thi Ngoc 2,  Sowndarya Muthukumar 2,  Gabriele Todisco 3,  Magdalena Madej 2,  Helena Fritz 2,  Marios Dimitriou 3,  Danny Incarnato 4,  Eva Hellström-Lindberg 3,  Cristian Bellodi 5
Affiliations

Affiliations

  • 1 Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden; International Institute of Molecular Mechanisms and Machines, Polish Academy of Sciences, Warsaw, Poland. Electronic address: m.ciesla@imol.institute.
  • 2 Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden.
  • 3 Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
  • 4 Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, the Netherlands.
  • 5 Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden. Electronic address: cristian.bellodi@med.lu.se.
PMID: 36944332 DOI: 10.1016/j.molcel.2023.02.024
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.

Keywords

ALKBH5; MYC; SF3B1; acute myeloid leukemia; alternative splicing; genome integrity; m(6)A; myelodysplastic syndromes; p53; translation.

Figures