Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia

Yusuke Shiozawa, Luca Malcovati, Anna Gallì, Aiko Sato-Otsubo, Keisuke Kataoka, Yusuke Sato, Yosaku Watatani, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Masashi Sanada, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Eva Hellström-Lindberg, Satoru Miyano, Seishi Ogawa () and Mario Cazzola ()
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Yusuke Shiozawa: The University of Tokyo
Luca Malcovati: University of Pavia
Anna Gallì: Fondazione IRCCS Policlinico San Matteo & University of Pavia
Aiko Sato-Otsubo: Kyoto University
Keisuke Kataoka: Kyoto University
Yusuke Sato: Kyoto University
Yosaku Watatani: Kyoto University
Hiromichi Suzuki: Kyoto University
Tetsuichi Yoshizato: Kyoto University
Kenichi Yoshida: Kyoto University
Masashi Sanada: Nagoya Medical Center
Hideki Makishima: Kyoto University
Yuichi Shiraishi: The University of Tokyo
Kenichi Chiba: The University of Tokyo
Eva Hellström-Lindberg: Karolinska Institutet
Satoru Miyano: The University of Tokyo
Seishi Ogawa: Kyoto University
Mario Cazzola: University of Pavia

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Spliceosome mutations are frequently found in myelodysplasia. Splicing alterations induced by these mutations, their precise targets, and the effect at the transcript level have not been fully elucidated. Here we report transcriptomic analyses of 265 bone marrow samples from myelodysplasia patients, followed by a validation using CRISPR/Cas9-mediated gene editing and an assessment of nonsense-mediated decay susceptibility. Small but widespread reduction of intron-retaining isoforms is the most frequent splicing alteration in SF3B1-mutated samples. SF3B1 mutation is also associated with 3′ splice site alterations, leading to the most pronounced reduction of canonical transcripts. Target genes include tumor suppressors and genes of mitochondrial iron metabolism or heme biosynthesis. Alternative exon usage is predominant in SRSF2- and U2AF1-mutated samples. Usage of an EZH2 cryptic exon harboring a premature termination codon is increased in both SRSF2- and U2AF1-mutated samples. Our study reveals a landscape of splicing alterations and precise targets of various spliceosome mutations.

Date: 2018
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DOI: 10.1038/s41467-018-06063-x

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