Elucidation of molecular mechanism through which MDS develops

• Project/Area Number: 15H04857
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Hiroshima University
• Principal Investigator: Inaba Toshiya 広島大学, 原爆放射線医科学研究所, 教授 (60281292)
• Co-Investigator(Kenkyū-buntansha): 長町 安希子 広島大学, 原爆放射線医科学研究所, 研究員 (20585153) ; 金井 昭教 広島大学, 原爆放射線医科学研究所, 助教 (60549567)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: MDS / RAEB / モノソミー７ / エンドソーム / Samd9/L / 7番染色体 / 細胞遊走能 / Haploinsufficiency / 中心体成熟不全 / Samd9 / Miki / haploinsufficiency

Outline of Final Research Achievements

To elucidate mechanisms through which a hematopoietic stem cell differentiates to mature blood cells, myelodysplastic syndromes (MDS) may be a good material. We identified three responsible genes for the deletion of the long arm of chromosome 7, which is most frequently observed as a non-random chromosome abnormality in patients with MDS. Both the homo- and hetero-deficient mice of Samd9/Samd9L genes, which encode endosome proteins developed MDS at their advanced age, mimics human diseases. Lack of Miki, which encodes a centrosome protein prolongs prometaphase, resulting in abnormal morphology of nuclei, which strikingly resembles those routinely observed in bone marrow preparations of MDS patients. Those three genes located in chromosome 7 were considered to be responsible for the development of MDS.

Research Products

• [Journal Article] A novel ASXL1?OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies (2018)
  • Author(s): Inoue D, Fujino T, Sheridan P, Zhang YZ, Nagase R, Horikawa S, Li Z, Matsui H, Kanai A, Saika M, Yamaguchi R, Kozuka-Hata H, Kawabata KC, Yokoyama A, Goyama S, Inaba T, Imoto S, Miyano S, Xu M, Yang FC, Oyama M, Kitamura T.
  • Journal Title: Leukemia Volume: 印刷中 Issue: 6 Pages: 1327-1337
  • DOI: 10.1038/s41375-018-0083-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dose-response curves for analyzing of dicentric chromosomes and chromosome translocation following doses of 1,000 mGy or less based on irradiated peripheral blood samples from 5 healthy individuals. (2018)
  • Author(s): Abe Y, Yoshida MA, Fujioka K, Kurosu Y, Ujiie R, Yanagi A, Tsuyama N, Miura T, Inaba T, Kamiya K, Sakai A
  • Journal Title: Journal of Radiation Research Volume: 59 Issue: 1 Pages: 35-42
  • DOI: 10.1093/jrr/rrx052
  • Peer Reviewed / Open Access
• [Journal Article] Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes. (2017)
  • Author(s): Kojo S, Tanaka H, Endo TA, Muroi S, Liu Y, Seo W, Tenno M, Kakugawa K, Naoe Y, Nair K, Moro K, Katsuragi Y, Kanai A, Inaba T, Egawa T, Venkatesh B, Minoda A, Kominami R, Taniuchi I.
  • Journal Title: Nat Commun. Volume: 8 Issue: 1 Pages: 702-702
  • DOI: 10.1038/s41467-017-00768-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers. (2017)
  • Author(s): Sugino N, Kawahara M, Tatsumi G, Kanai A, Matsui H, Yamamoto R, Nagai Y, Fujii S, Shimazu Y, Hishizawa M, Inaba T, Andoh A, Suzuki T, Takaori-Kondo A.
  • Journal Title: Leukemia Volume: in press Issue: 11 Pages: 2303-2314
  • DOI: 10.1038/leu.2017.59
  • Peer Reviewed
• [Journal Article] Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia (2017)
  • Author(s): Nakata Y, Ueda T, Nagamachi A, Yamasaki N, Ikeda KI, Sera Y, Takubo K, Kanai A, Oda H, Sanada M, Ogawa S, Tsuji K, Ebihara Y, Wolff L, Honda ZI, Suda T, Inaba T, Honda H.
  • Journal Title: Blood Volume: 129 Issue: 15 Pages: 2148-2160
  • DOI: 10.1182/blood-2016-06-724658
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency. (2017)
  • Author(s): Ikeda K, Ueda T, Yamasaki N, Nakata Y,Sera Y, Nagamachi A,Miyama T, Kobayashi H, Takubo K, Kanai A, Oda H, Wolff L, Honda Zi, Ichinohe T, Matsubara A, Suda T, Inaba T, Honda H.
  • Journal Title: Sci. Rep. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia. (2017)
  • Author(s): Nakata Y, Ueda U, Nagamachi A, Yamasaki N, Ikeda K, Sera Y, Takubo K, Kanai A, Oda H, Sanada M, Ogawa S, Tsuji K, Ebihara Y, Wolff L, Honda Z, Suda T, Inaba T, Honda H.
  • Journal Title: Blood Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice. (2016)
  • Author(s): Okubo H, Kushiyama A, Sakoda H, Nakatsu Y, Iizuka M, Taki N, Fujishiro M, Fukushima T, Kamata H, Nagamachi A, Inaba T, Nishimura F, Katagiri H, Asahara T, Yoshida Y, Chonan O, Encinas J, Asano T.
  • Journal Title: Sci. Rep. Volume: 6 Pages: 20157-20157
  • NAID: 120006796541
  • Peer Reviewed
• [Journal Article] Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia. (2016)
  • Author(s): Sera Y, Yamasaki N, Oda H, Nagamachi A, Wolff L, Inukai T, Inaba T, Honda H.
  • Journal Title: Cancer Sci. Volume: in press
  • Peer Reviewed
• [Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS. (2015)
  • Author(s): Inoue D, Kitaura J, Matsui H, Hou H-A, Chou W-C, Nagamachi A, Kawabata K, Togami K, Nagase R, Horikawa S, Saika M, Micol J-B, Hayashi Y, Harada Y, Harada H, Inaba T, Tien H-F, Abdel-Wahab O, Kitamura T.
  • Journal Title: Leukemia Volume: 29 Pages: 847-857
  • Peer Reviewed
• [Journal Article] Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2. (2015)
  • Author(s): Ueda T, Nagamachi A, Takubo K, Yamasaki N, Matsui H, Kanai A, Nakata Y, Ikeda K, Konuma T, Oda H, Wolff L, Honda ZI, Wu X, Helin K, Iwama A, Suda T, Inaba T, Honda H.
  • Journal Title: Blood Volume: 125 Pages: 3437-3446
  • Peer Reviewed
• [Presentation] MDS責任遺伝子Samd9/Samd9Lのエンドサイトーシス経路における機能解析 (2017)
  • Author(s): 1.長町安希子
  • Organizer: 日本血液学会総会
• [Presentation] The role of Samd9 and Samd9L in the early endocytotic pathway. (2017)
  • Author(s): Nagamachi A
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research
• [Presentation] Low Miki expression in myelodysplastic syndromes results in polynuclear cell formation through decondensation of chromosomes in prolonged prometaphase. (2015)
  • Author(s): Nagamachi A., Ozaki Y., Matsui H., Kanai A., Inaba T.
  • Organizer: The 57th American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-12-06
• [Presentation] eEF1A2 is a target gene of DNA demethylating agents for improving anemia of MDS (2015)
  • Author(s): Nagamachi A., Matsui H., Kanai A., Inaba T.
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-17
• [Presentation] Exploring haplo-insufficieny of multiple anti-oncogenes that facilitate malignant transformation (2015)
  • Author(s): Nagamachi A., Inaba T.
  • Organizer: The 74nd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-09
• [Presentation] 低線量率放射線照射による染色体異常出現頻度の解析 (2015)
  • Author(s): 長町安希子, 藤岡来実, 稲葉俊哉, 神谷研二
  • Organizer: 第56回原子爆弾後障害研究会
  • Place of Presentation: 広島
  • Year and Date: 2015-06-07
• [Presentation] Analysis of radiation induced mutations using next generation sequencer. (2015)
  • Author(s): Kanai, A.,Nagamachi A.,Kawai H.,Matsui H.,Kamiya K., Inaba T.
  • Organizer: ICRR
  • Place of Presentation: 京都
  • Year and Date: 2015-05-25