Molecular mechanisms of clonal expansion in myelodysplasia

• Project/Area Number: 24659458
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Kyoto University (2013); The University of Tokyo (2012)
• Principal Investigator: SANADA Masashi 京都大学, 医学(系)研究科(研究院), 助教 (20529044)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 骨髄異形成症候群 / RNAスプライシング / 遺伝子変異 / 造血幹細胞 / 老化

Research Abstract

Frequent pathway mutations involving multiple components of the RNA splicing machinery is considered one of the most important genetic events in MDS. But the molecular mechanisms of these alterations in the pathogenesis of MDS are still unknown. In this study we investigated the functional role of these mutants in hematopoiesis using mice model that focused on clonal expansion of mutated cells. We analyzed the hematological phenotype of Sf3b1 hetero mice, and SF3B1 plays an important role in the regulation of hematopoietic stem cells (HSCs), whereas SF3B1 haploinsufficiency is not associated with the MDS phenotype. Loss of function mutation of TET2 are often co-existed in MDS cases with RNA spliceosome mutation, and that we performed the competitive stem cell transplantation using spliceosome mutant transduced HSCs from TET2 knockout mice or wild type mice. But there are no evidence of growth advantage of HSCs with RNA spliceosome mutation in spite of TET2 deletion in this model.

Research Products

• [Journal Article] Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia. (2014)
  • Author(s): Matsunawa M, Yoshida K
  • Journal Title: Leukemia Volume: (Epub ahead of print) Issue: 9 Pages: 1-7
  • DOI: 10.1038/leu.2014.73
  • Peer Reviewed / Open Access
• [Journal Article] Landscape of genetic lesions in 944 patients with myel odysplastic 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) Issue: 2 Pages: 241-7
  • DOI: 10.1038/leu.2013.336
  • Peer Reviewed
• [Journal Article] Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations. (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: Haematologic Volume: 99 Issue: 1 Pages: 28-36
  • DOI: 10.3324/haematol.2013.091249
  • Peer Reviewed / Open Access
• [Journal Article] Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. (2014)
  • Author(s): Sakata-Yanagimoto M, Yoshida K
  • Journal Title: Nature Genet. Volume: 46 Issue: 2 Pages: 171-175
  • DOI: 10.1038/ng.2872
  • Peer Reviewed
• [Journal Article] 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: The Journal of Experimental Medicine Volume: 210(12) Issue: 12 Pages: 2627-39
  • DOI: 10.1084/jem.20131144
  • Peer Reviewed
• [Journal Article] Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. (2013)
  • Author(s): Kon A, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 10 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 Genet. Volume: 45 Issue: 8 Pages: 942-946
  • DOI: 10.1038/ng.2696
  • Peer Reviewed
• [Journal Article] BCOR and BCORL1 mutations in myelodysplastic synd romes 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) Issue: 18 Pages: 3169-77
  • DOI: 10.1182/blood-2012-11-469619
  • Peer Reviewed
• [Journal Article] The landscape of somatic mutations in Down syndrome-related myeloid disorders. (2013)
  • Author(s): Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 11 Pages: 1293-1200
  • DOI: 10.1038/ng.2759
  • 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 Acid Research Volume: 41 Issue: 7 Pages: e89-e89
  • DOI: 10.1093/nar/gkt126
  • Peer Reviewed
• [Journal Article] Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. (2013)
  • Author(s): Sakaguchi H, Yoshida K
  • Journal Title: Nature Genet. Volume: 46 Issue: 8 Pages: 937-941
  • 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 Issue: 2 Pages: 110-5
  • DOI: 10.1093/jjco/hys206
  • Peer Reviewed
• [Journal Article] ACTN1 Mutations Cause Congenital Macrothrombocytopenia (2013)
  • Author(s): 國島伸治、吉田健一
  • Journal Title: Am J Hum Genet Volume: 92 Issue: 3 Pages: 431-438
  • DOI: 10.1016/j.ajhg.2013.01.015
  • Peer Reviewed
• [Journal Article] Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia. (2013)
  • Author(s): Kon et al.
  • Journal Title: J. Clin. Invest. Volume: 123 Issue: 3 Pages: 1123-1137
  • DOI: 10.1172/jci63711
  • 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(12) Pages: 2557-60
• [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 Issue: 12 Pages: 2557-60
  • DOI: 10.1038/leu.2012.146
  • Peer Reviewed
• [Journal Article] Novel splicing-factor mutations in juvenile myelomonocytic leukemia (2012)
  • Author(s): 滝田順子、吉田健一
  • Journal Title: Leukemia Volume: 26 Issue: 8 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
  • NAID: 40019688461
  • Peer Reviewed
• [Presentation] Role Of Sf3b1 On Hematopoiesis (2013)
  • Author(s): Matsunawa M, Yamamoto R, Sanada M, Sato A, Shiozawa Y, Yoshida K, Nagata Y, Kon A, Yoshizato T, Otsu M, Isono K, Koseki H, Nakauchi H, Ogawa S.
  • Organizer: 55th Annual Meeting of American Society of Hematology
  • Place of Presentation: New Orleans
  • Year and Date: 2013-12-09
• [Presentation] Role of Sf3b1 on Hematopoiesis (2013)
  • Author(s): Matsunawa M, Yamamoto R, Sanada M, et al.
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-11
• [Presentation] Functional Analysis of Cohesin Mutations in Myeloid Neoplasms (2013)
  • Author(s): Kon A, Sanada M, et al.
  • Organizer: 18th Congress of the European Hematology Association
  • Place of Presentation: Stockholm
  • Year and Date: 2013-06-15
• [Presentation] AMLにおけるゲノム異常 (2013)
  • 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
• [Presentation] Novel pathway mutations in myelodysplasia revealed by high-throughput sequencing technology.
  • Author(s): 真田 昌
  • Organizer: 第７１回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Invited
• [Book] 「全エクソーム解析による骨髄異形成症候群の原因遺伝子の探索」別冊・医学のあゆみ「エクソーム解析―成果と将来」編集松本直通
  • Author(s): 真田昌
  • Publisher: 医歯薬出版