Molecular pathogenesis of spliceosome mutations in MDS

• Project/Area Number: 24390242
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto University (2013-2014); The University of Tokyo (2012)
• Principal Investigator: MASASHI Sanada 京都大学, 医学(系)研究科(研究院), 研究員 (20529044)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2012: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 骨髄異形成症候群 / RNAスプライシング / 造血幹細胞 / MDS / RNAシーケンス / モデルマウス / がん / ゲノム / 遺伝学 / マウスモデル / 遺伝子操作マウス / レトロウィルス

Outline of Final Research Achievements

Frequent mutation in RNA splicing factors is a cardinal feature of myelodysplastic syndromes. To understand their molecular mechanisms, we constructed model mice for these alterations in this study. In Sf3b1 hetero knockout mice and Srsf2 mutant conditional knock-in mice the number of hematopoietic stem cells are lower than those in wild type mice, and these repopulation capacities are also reduced. And RNA sequencing of hematopoietic stem/ progenitor cells from Srsf2 mutated mice showed abnormal exon usages in many genes. Thus, in conclusion, these findings suggest that RNA spliceosome mutations lead to deregulated hematopoietic stem cell functions likely due to abnormal RNA splicing.

Research Products

• [Journal Article] Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome (2015)
  • Author(s): Madan V, Kanojia D, Li J, Okamoto R, Sato-Otsubo A, Kohlmann A, Sanada M, Grossmann V, Sundaresan J, Shiraishi Y, Satoru M, Thol F, Ganser A, Yang H, Haferlach T, Ogawa S, Koeffler HP
  • Journal Title: Nat Commun Volume: ６ Pages: 6042-6042
  • DOI: 10.1038/ncomms7042
  • Peer Reviewed / Open Access
• [Journal Article] Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not tomyelodysplasia (2014)
  • Author(s): Matsunawa M, Yoshida K
  • Journal Title: Leukemia. Volume: (Epub ahead of print) Pages: 1844-1850
  • DOI: 10.1038/leu.2014.73
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome (2014)
  • Author(s): 7.Sato Y, Maekawa S, Ishii R, Sanada M, Morikawa T, Shiraishi Y, Yoshida K, Nagata Y, Sato-Otsubo A, Yoshizato T, Suzuki H, Shiozawa Y, Kataoka K, Kon A, Aoki K, Chiba K, Tanaka H, Kume H, Miyano S, Fukayama M, Nureki O, Homma Y, Ogawa S.
  • Journal Title: Science Volume: ３４４ Pages: 917-920
  • DOI: 10.1126/science.1252328
  • Peer Reviewed
• [Journal Article] Recurrent genetic defects on chromosome 7q in myeloid neoplasms. (2014)
  • Author(s): 10.Hosono N, Makishima H, Jerez A, Yoshida K, Przychodzen B, McMahon S, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Sanada M, Gómez-Seguí I, Verma AK, McDevitt MA, Sekeres MA, Ogawa S, Maciejewski JP.
  • Journal Title: Leukemia. Volume: ２８ Pages: 1348-1351
  • DOI: 10.1038/leu.2014.25
  • Peer Reviewed / Open Access
• [Journal Article] Somatic RHOA mutation in angioimmunoblastic T cell lymphoma (2014)
  • Author(s): Sakata-Yanagimoto M, Yoshida K
  • Journal Title: Nat Genet Volume: 46 Pages: 171-175
  • DOI: 10.1038/ng.2872
  • Peer Reviewed
• [Journal Article] Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. (2014)
  • Author(s): Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, Schnittger S, Sanada M, Kon A, Alpermann T, Yoshida K, Roller A, Nadarajah N, Shiraishi Y, Shiozawa Y, Chiba K, Tanaka H, Koeffler HP, Klein HU, Dugas M, Aburatani H, Kohlmann A, Miyano S, Haferlach C, Kern W, Ogawa S.
  • Journal Title: Leukemia Volume: 28(2) Pages: 4241-247
  • DOI: 10.1038/leu.2013.336
  • Peer Reviewed
• [Journal Article] Clonal leukemic evolution in myelodysplastic syndromes with TET2 and (2014)
  • Author(s): Lin, T. L. Nagata, Y. Kao, H. W. Sanada, M. Okuno, Y. Huang, C. F. Liang, D. C. Kuo, M. C. Lai, C. L. Lee, E. H. Shih, Y. S. Tanaka, H. Shiraishi, Y. Chiba, K. Lin, T. H. Wu, J. H. Miyano, S. Ogawa, S. Shih, L. Y.
  • Journal Title: Haematologica Volume: 99 Pages: 28-36
  • DOI: 10.3324/haematol.2013.091249
  • Peer Reviewed / Open Access
• [Journal Article] Landscape of gene mutations in Down syndrome-related myeloid disorders (2014)
  • Author(s): Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Nishimura R, Izraeli S, Hayashi Y, et al.
  • Journal Title: Nature genetics Volume: 45 Pages: 1293-1200
  • DOI: 10.1038/ng.2759
  • Peer Reviewed
• [Journal Article] A. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders (2013)
  • Author(s): Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, Sanada M, Miyagi S, Saraya A, Kamio A, Nagae G, Nakaseko C, Yokote K, Shimoda K, Koseki H, Suzuki Y, Sugano S, Aburatani H, Ogawa S, Iwama A.
  • Journal Title: J Exp Med. Volume: 210(12) Pages: 2627-2639
  • DOI: 10.1084/jem.20131144
  • Peer Reviewed
• [Journal Article] BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders (2013)
  • Author(s): Damm F, Chesnais V, Nagata Y, Yoshida K, Scourzic L, Okuno Y, Itzykson R, Sanada M, Shiraishi Y, Gelsi-Boyer V, Renneville A, Miyano S, Mori H, Shih LY, Park S, Dreyfus F, Guerci-Bresler A, Solary E, Rose C, Cheze S, Prebet T, Vey N, Legentil M, Duffourd Y, de Botton S, Preudhomme C, Birnbaum D, Bernard OA, Ogawa S, Fontenav M, Kosmider O.
  • Journal Title: Blood Volume: 122(18) Pages: 3169-3177
  • DOI: 10.1182/blood-2012-11-469619
  • Peer Reviewed
• [Journal Article] Recurrent mutations in multiple components of the cohesin complex inmyeloid neoplasms (2013)
  • Author(s): Kon A, Yoshida K
  • Journal Title: Nature Genetics Volume: 45 Pages: 1232-1237
  • DOI: 10.1038/ng.2731
  • Peer Reviewed
• [Journal Article] Somatic SETBP1 mutations in myeloid malignancies (2013)
  • Author(s): Makishima H, Yoshida K
  • Journal Title: Nature genetics Volume: 45 Pages: 942-6
  • DOI: 10.1038/ng.2696
  • Peer Reviewed
• [Journal Article] An empirical Bayesian framework for somatic mutation detection from cancer genome sequencing data. (2013)
  • Author(s): Yuichi Shiraishi
  • Journal Title: Nucleic Acids Research Volume: 41
  • DOI: 10.1093/nar/gkt126
  • Peer Reviewed
• [Journal Article] S.Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocyticleukemia (2013)
  • Author(s): Sakaguchi H, Yoshida K
  • Journal Title: Nature genetics Volume: 46 Pages: 3937-41
  • DOI: 10.1038/ng.2698
  • Peer Reviewed
• [Journal Article] Deep sequencing in cancer research. (2013)
  • Author(s): Yoshida K, Sanada M, Ogawa S.
  • Journal Title: Jpnj clin oncol. Volume: 432 Pages: 110-5
  • DOI: 10.1093/jjco/hys206
  • Peer Reviewed
• [Journal Article] ACTN1 mutations cause congenita macrothrombocytopenia (2013)
  • Author(s): 國島伸治、吉田健一
  • Journal Title: American journal of human genetics. Volume: 92 Pages: 431-438
  • DOI: 10.1016/j.ajhg.2013.01.015
  • Peer Reviewed
• [Journal Article] EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms (2012)
  • Author(s): Ueda T, Sanada M, Matsui H, Yamasaki N, Honda ZI, Shih LY, Mori H, Inaba T, Ogawa S, Honda H.
  • Journal Title: Leukemia Volume: 26 Pages: 2557-2560
  • DOI: 10.1038/leu.2012.146
  • Peer Reviewed
• [Journal Article] Novel splicing factor mutations in juvenile myelomonocytic leukenya. (2012)
  • Author(s): 滝田順子、吉田健一
  • Journal Title: Leukemia. Volume: 26 Pages: 1879-1881
  • DOI: 10.1038/leu.2012.45
  • Peer Reviewed
• [Journal Article] Genome-wide analysis of myelodysplastic syndromes. (2012)
  • Author(s): Sanada M, Ogawa S
  • Journal Title: Curr Pharm Des Volume: 18 Pages: 3163-3169
  • Peer Reviewed
• [Presentation] Comprehensive Analysis of Alternative RNA Splicing in Myelodysplastic Syndrome (2014)
  • Author(s): Yusuke Shiozawa, Sato Sato-Otsubo, Anna Gallì, Kenichi Yoshida, Tetsuichi Yoshizato, Yusuke Sato, Keisuke Kataoka,Masashi Sanada,Yuichi Shiraishi, Kenichi Chiba, Satoru Miyano, Luca Malcovati, Mario Cazzola, and Seishi Ogawa
  • Organizer: 56th American Society of Hematology 2014 Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-05 – 2014-12-09
• [Presentation] ZRSR2 Mutations Cause Dysregulated RNA Splicing in MDS (2014)
  • Author(s): Vikas Madan, Deepika Kanojia, Li Jia, Ryoko Okamoto, Aiko Sato-Otsubo, Alexander Kohlmann, Masashi Sanada, Vera Grossmann, Janani Sundaresan, Yuichi Shiraishi, Satoru Miyano, Felicitas Thol, Arnold Ganser, Henry Yang, Torsten Haferlach, Seishi Ogawa, and H. Phillip Koeffler
  • Organizer: 56th American Society of Hematology 2014 Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-05 – 2014-12-09
• [Presentation] SF3B1 PLAYS AN IMPORTANT ROLE IN THE REGULATION OF HEMATOPOIETIC STEMS CELLS, BUT HAPLOINSUFFICIENCY OF SF3B1 MAY NOT BE SOLELY RESPONSIBLE FOR MYELODYSPLASIA (2014)
  • Author(s): Manabu Matsunawa, Ryo Yamamoto, Masashi Sanada, Ayana Kon, Aiko Sato-Otsubo, Yusuke Shiozawa, Kenichi Yoshida, Yasunobu Nagata, Tetsuichi Yoshizato, Makoto Otsu, Kyoichi Isono, Haruhiko Koseki, Hiromitsu Nakauchi, Seishi Ogawa
  • Organizer: The 19th Congress of European Hematology Association
  • Place of Presentation: Milan, Italy
  • Year and Date: 2014-06-12 – 2014-06-15
• [Presentation] Novel pathway mutations in myelodysplasia revealed by high-throughput sequencing technology. (2012)
  • Author(s): 真田昌
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市(招待講演)
  • Year and Date: 2012-09-20
• [Presentation] AMLにおけるゲノム異常
  • Author(s): 眞田 昌
  • Organizer: 第７５回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Invited
• [Presentation] Role Of Sf3b1 On Hematopoiesis
  • Author(s): Manabu Matsunawa, Ryo Yamamoto, Masashi Sanada, Aiko Sato, Yusuke Shiozawa, Kenichi Yoshida, Yasunobu Nagata, Ayana Kon, Tetsuichi Yoshizato, Makoto Otsu, Kyoichi Isono, Haruhiko Koseki, Hiromitsu Nakauchi, and Seishi Ogawa
  • Organizer: 55th Annual Meeting of American Society of Hematology
  • Place of Presentation: New Orleans
• [Presentation] FUNCTIONAL ANALYSIS OF COHESIN MUTATIONS IN MYELOID NEOPLASMS
  • Author(s): Ayana Kon, Masashi Sanada, et al. (2/20)
  • Organizer: 18th Congress of the European Hematology Association
  • Place of Presentation: Stockholm
• [Presentation] Role Of Sf3b1 On Hematopoiesis
  • Author(s): Manabu Matsunawa, Ryo Yamamoto, Masashi Sanada, Aiko Sato, Yusuke Shiozawa, Kenichi Yoshida, Yasunobu Nagata, Ayana Kon, Tetsuichi Yoshizato, Makoto Otsu, Kyoichi Isono, Haruhiko Koseki, Hiromitsu Nakauchi, and Seishi Ogawa
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Book] 医学のあゆみVol.249 No.10特集 がんゲノム研究の進歩ー網羅的解析からの知見 (2014)
  • Author(s): 眞田 昌
  • Total Pages: 129
  • Publisher: 医歯薬出版