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Research on the functional assignment of the IKZF transcription factor by structural difference and on the modulation of transcriptional regulation by mutations in the IKZF1 molecule

Research Project

Project/Area Number 21H02879
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Morio Tomohiro  東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30239628)

Co-Investigator(Kenkyū-buntansha) 尾崎 富美子  東京医科歯科大学, 大学院医歯学総合研究科, プロジェクト助教 (60795277)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2021: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywords原発性免疫不全症 / リンパ球分化 / 転写調節 / ダイマー / イカロス / アイオロス / arosファミリー分子 / Ikarosファミリー分子
Outline of Research at the Start

IKZFファミリー分子は造血細胞系に発現し、その異常は免疫異常症やリンパ系悪性腫瘍の発症に関与している。一方、ホモダイマー、ヘテロダイマーの機能差異や、変異部位により異なる表現型の分子病態は未だに不明である。本研究では、IKZF1, 3を中心に、ホモダイマー、ヘテロダイマーの機能を検証する系を確立し、構造による機能差異を明らかにし、さらにモノマーの機能や、isoformの時空間的・機能的解析に研究を展開する。病態解析としては疾患でのIKZF3変異を中心として、分子動態の修飾や、疾患発生の分子機構を明らかにする。また、転写因子異常症での遅発性発症の分子機構につき、制御領域の経時的変化や後成的修飾を明らかにする。

Outline of Final Research Achievements

In this study, we introduced the split GFP and split AirID systems to clarify the functional differences between homo- and hetero-dimers and found that these systems work in adherent cells. We also generated Ikzf3 G159R, N160S, Ikzf1 N159S mice, and etc., and performed detailed phenotyping in bone marrow, and secondary lymphoid tissues. We also examined in detail the differential dysregulation of expression caused by each mutation. We found that Ikzf3 G159R and N160S have independent dysfunctions, and that at least Ikzf3 N160S plays a part in the pathogenesis by inhibiting Ikzf1 function and hematopoietic cell homing. Long-term follow-up of these mice and sampling of cells and nucleic acids over time was done, which will enable us to analyze mutation accumulation and the change in the accessibility of transcription factors. In addition, several novel IKZF3 mutations were identified from international collaborations; and functional analysis of the mutant molecules was performed.

Academic Significance and Societal Importance of the Research Achievements

まず今まで明らかでなかった先天性免疫異常症の責任遺伝子、遺伝子変異が明らかになり、疾患の理解に繋がった。国際共同研究からIKZF3以外の分子の異常も判明した。また、IKZFファミリータンパクの異常による易感染性、自己免疫疾患、悪性腫瘍発症の分子機能を知ることは、これらの疾患の一般的な分子病態の解明や、治療法の開発に繋がると期待される。さらに、ホモダイマー、ヘテロダイマーを形成する転写因子の機能的差異が明らかになれば、発生や分化、腫瘍発生等の分子機能がより明確になり、生体内における分子間相互作用や、複雑な転写制御の理解の一助になると予想される。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (18 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (7 results) Journal Article (8 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Int'l Joint Research] Department of Pediatrics,/Division of Allergy- Immunology,/Sakarya University(トルコ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] St. Giles Laboratory of Human/Human Genetics of Infectious Diseases/The Rockefeller University(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Pediatrics //Pediatric Hematology and Oncology //Immunology (DGfI) LMU Klinikum(ドイツ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Pediatric Rheumatology Unit/and National Referee Centre RAISE HFME,/HCL, Lyon, France(フランス)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Department of Laboratory Medicine,/Clinical Center、NIH(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Department of Pediatrics,/Division of Allergy- Immunology,/Sakarya University(トルコ)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Department of Laboratory Medicine,/Clinical Center、NIH/Sergio D. Rosenzweig, MD, PhD.(米国)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] A Rare AIOLOS N160S Variant Causing IEI in Human2024

    • Author(s)
      Ozdemir Oner、Dikici Ummugulsum、Yarar Murat Hakki、Yamashita Motoi、Morio Tomohiro
    • Journal Title

      Journal of Clinical Immunology

      Volume: 44 Issue: 2 Pages: 57-57

    • DOI

      10.1007/s10875-024-01657-1

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] AIOLOS-associated Inborn Errors of Immunity.2024

    • Author(s)
      Yamashita M, Morio T.
    • Journal Title

      J Clin Immunol.

      Volume: 44(6) Issue: 6 Pages: 128-128

    • DOI

      10.1007/s10875-024-01730-9

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Initial manifestations in Patients with Inborn Errors of Immunity Based on Onset Age: a Study from a Nationwide Survey in Japan2023

    • Author(s)
      Kido Takahiro、Hosaka Sho、Imagawa Kazuo、Fukushima Hiroko、Morio Tomohiro、Nonoyama Shigeaki、Takada Hidetoshi
    • Journal Title

      Journal of Clinical Immunology

      Volume: 43 Issue: 4 Pages: 747-755

    • DOI

      10.1007/s10875-023-01434-6

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee.2022

    • Author(s)
      Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, Klein C, Morio T, Oksenhendler E, Picard C, Puel A, Puck J, Seppanen MRJ, Somech R, Su HC, Sullivan KE, Torgerson TR, Meyts I.
    • Journal Title

      J Clin Immunol.

      Volume: 42 Issue: 7 Pages: 1-35

    • DOI

      10.1007/s10875-022-01289-3

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] AIOLOS Variants Causing Immunodeficiency in Human and Mice2022

    • Author(s)
      Yamashita Motoi、Morio Tomohiro
    • Journal Title

      Frontiers in Immunology

      Volume: 13 Pages: 866582-866582

    • DOI

      10.3389/fimmu.2022.866582

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients2021

    • Author(s)
      Kuehn Hye Sun、Chang Jingjie、Yamashita Motoi、Niemela Julie E.、Zou Chengcheng、Okuyama Kazuki、Harada Junji、Stoddard Jennifer L.、Nunes-Santos Cristiane J.、Boast Brigette、Baxter Ryan M.、Hsieh Elena W.Y.、Garofalo Mary、Fleisher Thomas A.、Morio Tomohiro、Taniuchi Ichiro、Dutmer Cullen M.、Rosenzweig Sergio D.
    • Journal Title

      Journal of Experimental Medicine

      Volume: 218 Issue: 12

    • DOI

      10.1084/jem.20211118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS2021

    • Author(s)
      Yamashita Motoi、Kuehn Hye Sun、Okuyama Kazuki、Okada Satoshi、Inoue Yuzaburo、Takagi Masatoshi、Kanegane Hirokazu、Takeuchi Masahiro、Shimojo Naoki、Tsumura Miyuki、Padhi Aditya K.、Zhang Kam Y. J.、Boisson Bertrand、Casanova Jean-Laurent、Ohara Osamu、Rosenzweig Sergio D.、Taniuchi Ichiro、Morio Tomohiro
    • Journal Title

      Nature Immunology

      Volume: 22 Issue: 7 Pages: 893-903

    • DOI

      10.1038/s41590-021-00951-z

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inborn errors of IKAROS and AIOLOS.2021

    • Author(s)
      Yamashita M and Morio T.
    • Journal Title

      Curr Opin Immunol .

      Volume: 72 Pages: 239-248

    • DOI

      10.1016/j.coi.2021.06.010

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Presentation] Dissection of the molecular pathogenesis of transcription factor defects using model mice/cell systems.2023

    • Author(s)
      Morio T.
    • Organizer
      Chang Gung Medical Week Symposium.
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Novel gene discovery.2023

    • Author(s)
      Morio T.
    • Organizer
      Asia Pacific Society for Immunodeficiencies (APSID).
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of the molecular pathogenesis of human inborn errors of immunity.2021

    • Author(s)
      Morio T
    • Organizer
      The 50th Annual Meeting of Japanese Society of Immunology
    • Related Report
      2021 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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