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Abnormal endosomal traffic induced by Samd9/9L causing myelodysplastic syndromes and inherited bone marrow failure

Research Project

Project/Area Number 18H02838
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionHiroshima 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, 助教 (20585153)
松井 啓隆  熊本大学, 大学院生命科学研究部(医), 教授 (60379849)
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) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords骨髄異形成症候群 / 造血不全 / モノソミー7 / サイトカイン / Samd9/9L / エンドソーム / 受容体代謝 / MDS / Samd9/9L / サイトカイン受容体 / トランスフェリン / Samd9/L / 表面受容体代謝 / 造血障害 / エンドソーム交通
Outline of Final Research Achievements

Samd9 and Samd9L (hereafter Samd9/9L) are leukemia- and MDS- suppressor genes on 7q. Recent studies have indicated that gain-of-function mutations cause multiple organ failure including inherited bone marrow failure syndromes that are now designated as "Samd9/9L syndrome". Using Crispr/Cas9 technology, we established and analyzed a mice model carrying one of the causing mutations. The endocytosis of ligand-bound growth factors, as well as transferrin receptors was perturbed in the bone marrow, testis and kidney. In addition, enhanced lysosome function promoted cytokine receptor metabolism.

Academic Significance and Societal Importance of the Research Achievements

骨髄異形成症候群(MDS)は、白血病と同程度の頻度であり、血液疾患として稀なものではないが、かつて「不応性貧血」とか「くすぶり型白血病」とか呼ばれていたことが端的に示すように、造血不全と腫瘍の両方の性格を持つ難治性疾患である。Samd9/9L遺伝子は、その欠損がMDSを発症することが知られていたが、今回その機能亢進が造血不全を引き起こすことがヒトとマウスで確認された。MDSという難解な疾患の本質に迫る手がかりを与える研究成果であり、海外の研究者からも大きな反響があった。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (23 results)

All 2021 2020 2019 2018

All Journal Article (14 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 14 results,  Open Access: 12 results) Presentation (9 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] Multi-organ failure with abnormal receptor metabolism in mice mimicking Samd9/9L syndromes2021

    • Author(s)
      Nagamachi A, Kanai A, Nakamura M, Okuda H, Yokoyama A, Shinriki S, Matsui H, Inaba T.
    • Journal Title

      J Clin Invest

      Volume: 131 Issue: 4 Pages: 1-16

    • DOI

      10.1172/jci140147

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Revertant somatic mosaicism as a cause of cancer2021

    • Author(s)
      Inaba Toshiya、Nagamachi Akiko
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 4 Pages: 1383-1389

    • DOI

      10.1111/cas.14852

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] HHEX promotes myeloid transformation in cooperation with mutant ASXL1.2020

    • Author(s)
      Takeda R, Asada S, Park SJ, Yokoyama A, Becker H, Kanai A, Visconte V, Hershberger C, Hayashi Y, Yonezawa T, Tamura M, Fukushima T, Tanaka Y, Fukuyama T, Matsumoto A, Yamasaki S, Nakai K, Yamazaki S, Inaba T, Shibata T, Inoue D, Honda H, Goyama S, Maciejewski J, Kitamura T.
    • Journal Title

      Blood

      Volume: 136 Pages: 1670-1684

    • DOI

      10.1182/blood.2019004613

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] High prevalence of MEF2D fusion in human B-cell precursor acute lymphoblastic leukemia cell lines.2020

    • Author(s)
      Akahane K, Yasuda T, Tsuzuki S, Hayakawa F, Kiyokawa N, Somazu S, Watanabe A, Kagami K, Abe M, Harama D, Goi K, Kawazu M, Kojima S, Imamura T, Goto H, Iwamoto S, Minegishi M, Abe M, Hojo H, Inaba T, Mano H, Sugita K, Inukai T.
    • Journal Title

      Hematol Oncol.

      Volume: 38 Issue: 4 Pages: 614-617

    • DOI

      10.1002/hon.2762

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL2020

    • Author(s)
      Atsushi Watanabe, Kunio Miyake, Jessica Nordlund, Ann-Christine Syvanen, Louise van der Weyden, Hiroaki Honda, Norimasa Yamasaki, Akiko Nagamachi, Toshiya Inaba, Tomokatsu Ikawa, Kevin Y Urayama, Nobutaka Kiyokawa, Akira Ohara, Shunsuke Kimura, Yasuo Kubota, Junko Takita, Hiroaki Goto, Kimiyoshi Sakaguchi, et al.
    • Journal Title

      Blood

      Volume: 136 Issue: 20 Pages: 2319-2333

    • DOI

      10.1182/blood.2019004090

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of Radiation on Blood Pressure and Body Weight in the Spontaneously Hypertensive Rat Model. Are Radiation Effects on Blood Pressure Affected by Genetic Background?2020

    • Author(s)
      105.Takahashi N, Misumi M, Niwa Y, Murakami H, Ohishi W, Inaba T, Nagamachi A, Tanaka S, Iii IBT, Suzuki G.
    • Journal Title

      Radiat Res.

      Volume: in press Issue: 6 Pages: 552-552

    • DOI

      10.1667/rr15536.1

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status.2020

    • Author(s)
      Shrestha R, Sakata-Yanagimoto M, Maie K, Oshima M, Ishihara M, Suehara Y, Fukumoto K,1 Nakajima-Takagi Y, Matsui H, Kato T, Muto H, Sakamoto T, Kusakabe M, Nannya Y, Makishima H, Ueno H, Saiki R, Ogawa S, Chiba K, Shiraishi Y, Miyano S, Mouly E, Bernard OA, Inaba T, Koseki H, Iwama A, Chiba S
    • Journal Title

      Blood Adv.

      Volume: 4(5) Issue: 5 Pages: 845-854

    • DOI

      10.1182/bloodadvances.2019001324

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction2020

    • Author(s)
      Kobatake Kohei et al., Honda Zen-ichiro et al. and Honda Hiroaki
    • Journal Title

      Clinical Cancer Research

      Volume: 26 Issue: 8 Pages: 2065-2079

    • DOI

      10.1158/1078-0432.ccr-19-2230

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] BRD4-Regulated Molecular Targets in Mantle Cell Lymphoma: Insights into Targeted Therapeutic Approach2019

    • Author(s)
      TSUKAMOTO TAKU、NAKAHATA SHINGO、SATO RYUICHI、KANAI AKINORI、NAKANO MASAKAZU、CHINEN YOSHIAKI、MAEGAWA-MATSUI SAORI、MATSUMURA-KIMOTO YAYOI、TAKIMOTO-SHIMOMURA TOMOKO、MIZUNO YOSHIMI、KUWAHARA-OTA SAEKO、KAWAJI YUKA、TANIWAKI MASAFUMI、INABA TOSHIYA、TASHIRO KEI、MORISHITA KAZUHIRO、KURODA JUNYA
    • Journal Title

      Cancer Genomics - Proteomics

      Volume: 17 Issue: 1 Pages: 77-89

    • DOI

      10.21873/cgp.20169

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kinetics of cytokine receptor internalization under steady-state conditions affects growth of neighboring blood cells.2019

    • Author(s)
      Nagamachi A, Kikuchi J, Kanai A, Furukawa Y, Inaba T.
    • Journal Title

      Haematologica

      Volume: in press Issue: 7 Pages: 1-14

    • DOI

      10.3324/haematol.2019.232959

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Resistance of t(17;19)-acute lymphoblastic leukemia cell lines to multiagents in induction therapy.2019

    • Author(s)
      Watanabe A, Inukai T, Kagami K, Abe M, Takagi M, Fukushima T, Fukushima H, Nanmoku T, Terui K, Ito T, Toki T, Ito E, Fujimura J, Goto H, Endo M, Look T, Kamps M, Minegishi M, Takita J, Inaba T, Takahashi H, Ohara A, Harama D, Shinohara T, Somazu S, Oshiro H, Akahane K, Goi K, Sugita K.
    • Journal Title

      Cancer Med.

      Volume: 7 Issue: 11 Pages: 5274-5288

    • DOI

      10.1002/cam4.2356

    • NAID

      120007159553

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / 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

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel ASXL1?OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies2018

    • 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

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The enigma of monosomy 7.2018

    • Author(s)
      97.Inaba T, Honda H, Matsui H.
    • Journal Title

      Blood

      Volume: 131 Issue: 26 Pages: 2891-2898

    • DOI

      10.1182/blood-2017-12-822262

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] Abnormal receptor metabolism by Samd9/9L mutations is a cause of MIRAGE syndrome. Samd9/9L変異体による受容体取込み異常がMIRAGE症候群の骨髄・多臓器不全をもたらす2020

    • Author(s)
      Akiko Nagamachi, Hirotaka Matsui, Akinori Kanai, Satoru Shinriki, Toshiya Inaba.
    • Organizer
      日本血液学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Abnormal endocytosis due to a Samd9L mutation causes bone marrow/multi-organ failure in mice mimicking MIRAGE syndrome.モノソミー7を伴うMDSを多発するMIRAGE症候群モデルマウスに見られた受容体取込み異常2020

    • Author(s)
      Akiko Nagamachi, Hirotaka Matsui, Akinori Kanai, Satoru Shinriki, and Toshiya Inaba.
    • Organizer
      日本癌学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Internalization speed of surface cytokine receptors is critical for hematopoietic cell growth. サイトカイン受容体取込み速度が造血細胞の競合に与える影響:モノソミー7を有するMDSの発症機序2020

    • Author(s)
      Toshiya Inaba, Akiko Nagamachi, Akinori Kanai, Jiro Kikuchi, Yusuke Furukawa.
    • Organizer
      日本癌学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 表面受容体の代謝スピード異常:モデルマウスから読み解くモノソミー7とSamd9/9L症候群の病態2020

    • Author(s)
      稲葉俊哉
    • Organizer
      日本小児血液がん学会(シンポジウム)
    • Related Report
      2020 Annual Research Report
  • [Presentation] The role of endosomal proteins, Samd9 and Samd9L, in hematopoiesis and myeloid diseases carrying monosomy 7.2019

    • Author(s)
      Akiko Nagamachi, Hirotaka Matsui, Satoru Shinriki, Akinori Kanai, Toshiya Inaba
    • Organizer
      日本癌学会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Regulation of receptor internalization by Samd9/Samd9L and their mutants2019

    • Author(s)
      Akiko Nagamachi, Hirotaka Matsui, Satoru Shinriki, Akinori Kanai, Toshiya Inaba
    • Organizer
      日本血液学会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] モノソミー7:どこまでわかったか2019

    • Author(s)
      稲葉俊哉、長町安希子
    • Organizer
      日本血液学会(教育講演)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Roles of Samd9/L in MDS associated with monosomy 72018

    • Author(s)
      長町安希子
    • Organizer
      日本癌学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Samd9/Samd9L変異体による造血障害メカニズムの解明2018

    • Author(s)
      長町安希子
    • Organizer
      日本血液学会
    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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