TY - JOUR
T1 - m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis.
AU - Cieśla, Maciej
AU - Ngoc, Phuong Cao Thi
AU - Muthukumar, Sowndarya
AU - Todisco, Gabriele
AU - Madej, Magdalena
AU - Fritz, Helena
AU - Dimitriou, Marios
AU - Incarnato, Danny
AU - Hellström-Lindberg, Eva
AU - Bellodi, Cristian
N1 - Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
U2 - 10.1016/j.molcel.2023.02.024
DO - 10.1016/j.molcel.2023.02.024
M3 - Article
C2 - 36944332
SN - 1097-2765
VL - 83
SP - 1165
EP - 1179
JO - Molecular Cell
JF - Molecular Cell
ER -