SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes.

Autor:	Lieu YK; Department of Biological Sciences, Columbia University, New York, NY 10027; ylieu6@gmail.com jlm2@columbia.edu sm3252@cumc.columbia.edu.; Irving Cancer Research Center, Columbia University, New York, NY 10032., Liu Z; Chinese Academy of Sciences Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences 100101 Beijing, China.; Department of Systems Biology, Columbia University, New York, NY 10032.; Department of Biomedical Informatics, Columbia University, New York, NY 10032.; Program for Mathematical Genomics, Columbia University, New York, NY 10032., Ali AM; Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, NY 10032., Wei X; Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065.; Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450008, China., Penson A; Department of Systems Biology, Columbia University, New York, NY 10032.; Department of Biomedical Informatics, Columbia University, New York, NY 10032., Zhang J; Department of Biological Sciences, Columbia University, New York, NY 10027., An X; Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065., Rabadan R; Department of Systems Biology, Columbia University, New York, NY 10032.; Department of Biomedical Informatics, Columbia University, New York, NY 10032.; Program for Mathematical Genomics, Columbia University, New York, NY 10032., Raza A; Irving Cancer Research Center, Columbia University, New York, NY 10032.; Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, NY 10032., Manley JL; Department of Biological Sciences, Columbia University, New York, NY 10027; ylieu6@gmail.com jlm2@columbia.edu sm3252@cumc.columbia.edu., Mukherjee S; Irving Cancer Research Center, Columbia University, New York, NY 10032; ylieu6@gmail.com jlm2@columbia.edu sm3252@cumc.columbia.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Jan 04; Vol. 119 (1).
DOI:	10.1073/pnas.2111703119
Abstrakt:	SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations. Competing Interests: Competing interest statement: Y.K.L., J.Z., J.L.M., and S.M. are supported in part by a grant from Celgene Pharmaceutical Company (currently Bristol Myers Squibb); R.R. is a member of the AimedBio SAB and a founder of Genotwin. None of the work is directly related to the current manuscript. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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