TY - JOUR
T1 - Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia
AU - Shiozawa, Yusuke
AU - Malcovati, Luca
AU - Gallì, Anna
AU - Sato-Otsubo, Aiko
AU - Kataoka, Keisuke
AU - Sato, Yusuke
AU - Watatani, Yosaku
AU - Suzuki, Hiromichi
AU - Yoshizato, Tetsuichi
AU - Yoshida, Kenichi
AU - Sanada, Masashi
AU - Makishima, Hideki
AU - Shiraishi, Yuichi
AU - Chiba, Kenichi
AU - Hellström-Lindberg, Eva
AU - Miyano, Satoru
AU - Ogawa, Seishi
AU - Cazzola, Mario
N1 - Funding Information:
This work was supported by the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT, 16cm0106501h0001), Practical Research for Innovative Cancer Control (15Ack0106014h0002, 16ck0106073h0003), and Project for Cancer Research and Therapeutic Evolution (P-CREATE, 16cm0106501h0001) from Japan Agency for Medical Research and Development (AMED) to S.O., Japan Society for the Promotion of Science (JSPS) KAKENHI (15J02911 to Y. Shiozawa; 15H05668 to K.Y.; 26115009 to M.S.; 22134006, 26221308, and 15H05909 to S.O.), research grants from Associazione Italiana per la Ricerca sul Cancro (AIRC, Special Program Molecular Clinical Oncology 5 per Mille, project 1005 to M.C.; IG 15356 and 20125 to L.M.) and from Fondazione Regionale Ricerca Biomedica (FRRB, project no. 2015-0042 to M.C.), those from the Swedish Cancer Society and the Research Council of Sweden to E.H-L., and those from the Uehara Memorial Foundation to K.Y. This research used computational resources of the Human Genome Center, the Institute of Medical Science, The University of Tokyo, Japan, and those of the K computer provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project (hp160219). We are grateful to all the patients for their participation in this study.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-06063-x
DO - 10.1038/s41467-018-06063-x
M3 - Article
C2 - 30194306
AN - SCOPUS:85053014617
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3649
ER -