Molecular mechanisms of clonal expansion in myelodysplasia

2013 Fiscal Year Final Research Report

• 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
• Keywords: 骨髄異形成症候群 / RNAスプライシング

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, Yamamoto R, Sanada M, Sato-Otsubo A, Shiozawa Y, Yoshida K, Otsu M, Shiraishi Y, Miyano S, Isono K, Koseki H, Nakauchi H, Ogawa S.
  • Journal Title: Leukemia Volume: (in press)
  • DOI: 10.1038/leu.2014.73
• [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: 241-7
  • DOI: 10.1038/leu.2013.336
• [Journal Article] Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations (2014)
  • Author(s): Lin TL, Nagata Y, Kao HW, Sanada M, Okuno Y, Huang CF, Liang DC, Kuo MC, Lai CL, Lee EH, Shih YS, Tanaka H, Shiraishi Y, Chiba K, Lin TH, Wu JH, Miyano S, Ogawa S, Shih LY.
  • Journal Title: Haematologica Volume: 99(1) Pages: 28-36
  • DOI: 10.3324/haematol.2013.091249
• [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: J Exp Med Volume: 210(12) Pages: 2627-39
  • DOI: 10.1084/jem.20131144
• [Journal Article] Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms (2013)
  • Author(s): Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y, Yoshida K, Okuno Y, Bando M, Nakato R, Ishikawa S, Sato-Otsubo A, Nagae G, Nishimoto A, Haferlach C, Nowak D, Sato Y, Alpermann T, Nagasaki M, Shimamura T, Tanaka H, Chiba K, Yamamoto R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Nakamaki T, Ishiyama K, Nolte F, Hofmann WK, Miyawaki S, Chiba S, Mori H, Nakauchi H, Koeffler HP, Aburatani H, Haferlach T, Shirahige K, Miyano S, Ogawa S.
  • Journal Title: Nat Genet Volume: 45(10) Pages: 1232-7
  • DOI: 10.1038/ng.2731
• [Journal Article] Somatic SETBP1 mutations in myeloid malignancies (2013)
  • Author(s): Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, Ng KP, Gudmundsson KO, Vishwakarma BA, Jerez A, Gomez-Segui I, Takahashi M, Shiraishi Y, Nagata Y, Guinta K, Mori H, Sekeres MA, Chiba K, Tanaka H, Muramatsu H, Sakaguchi H, Paquette RL, McDevitt MA, Kojima S, Saunthararajah Y, Miyano S, Shih LY, Du Y, Ogawa S, Maciejewski JP.
  • Journal Title: Nat Genet Volume: 45(8) Pages: 942-6
  • DOI: 10.1038/ng.2696
• [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
• [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
• [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