• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Analysis of tumor microenvironment in aggressive NK leukemia

Research Project

Project/Area Number 20H03716
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 InstitutionTokai University

Principal Investigator

Kotani Ai  東海大学, 医学部, 教授 (00517477)

Co-Investigator(Kenkyū-buntansha) 前田 高宏  九州大学, 医学研究院, 教授 (00791972)
半田 寛  群馬大学, 大学院医学系研究科, 准教授 (90282409)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2020: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
KeywordsアグレッシブNK白血病 / Epstein Bar virus / 劇症型NK白血病 / EBV / 白血病 / PDXマウス / トランスフェリン / システイン / がん微小環境
Outline of Research at the Start

EBウイルス(EBV)関連癌であるアグレッシブNK細胞白血病(ANKL)は、その稀少性や急激な進行のため病態解析が進まず、生存中央値2ヶ月という極めて予後不良な疾患である。これまでに腫瘍微小環境を含む包括的なANKL病態解析を可能とする異種移植モデル(PDX)マウスをANKL2症例に対して構築し、腫瘍進展の首座が肝臓の類洞であることが明らかにした。類洞の特徴を表す分子対や先行研究でEBV関連癌での重要性を示した骨髄系細胞の遊走に関与する分子対などを含む約50種類の分子対が同定し、in vivo CRISPR Screeningによって機能解析を包括的かつ詳細に行い、治療標的を同定する。

Outline of Final Research Achievements

To comprehensively analyze the microenvironment of aggressive NK leukemia, a rare disease, for which there is no standard treatment, we constructed 6 PDX mice and performed interlactome analysis using human and mouse RNA sequence differences with a focus on the microenvironment in 3 of the mice that can be analyzed stably. We performed an exhaustive screening using several in silico analysis software programs and selected 10 candidate gene pairs for therapeutic targets. In particular, administration of anti-human TfnR antibody markedly prolonged survival, and a physician-initiated study was initiated in fiscal year 2005 with the support of AMED's "Drug Discovery Support Promotion Program and Pre-designation Commercialization Support Program for Orphan Drugs".

Academic Significance and Societal Importance of the Research Achievements

アグレッシブNK白血病は、本邦では、年間発症数が20人から30人という希少疾患であり、進行が早く、生存中央値は2ヶ月未満である。希少疾患故、病態解析が進まず、標準治療法がない。しかし、AYA世代を含む若年者に発症する特徴や欧米では更に頻度が低いため、我が国から治療法開発をしていくべき疾患である。臨床治験を開始するところまで、研究成果をつなげられた本研究の社会的意義は極めて高いと考えられる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (17 results)

All 2023 2022 2021 2020

All Journal Article (15 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 15 results,  Open Access: 10 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Hepatic niche leads to aggressive natural killer cell leukemia proliferation through transferrin transferrin receptor 1 axis.2023

    • Author(s)
      Kameda K, Yanagiya R, *Kotani A. (29名中29番目)
    • Journal Title

      Blood in press

      Volume: in press

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Secreted phospholipase A2 modifies extracellular vesicles and accelerates B cell lymphoma.2022

    • Author(s)
      Kudo K, Miki Y, *Kotani A. (16名中16番目)
    • Journal Title

      Cell Metab.

      Volume: 34 Pages: 615-633

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Human hepatocyte-derived extracellular vesicles attenuate the carbon tetrachloride-induced acute liver injury in mice2021

    • Author(s)
      Kakizaki Masatoshi、Yamamoto Yuichiro、Nakayama Shunya、Kameda Kazuaki、Nagashima Etsuko、Ito Masatoshi、Suyama Takashi、Matsuzaki Yumi、Chiba Tetsuhiro、Sumiyoshi Hideaki、Inagaki Yutaka、Kotani Ai
    • Journal Title

      Cell Death and Disease

      Volume: 12 Issue: 11 Pages: 1010-1010

    • DOI

      10.1038/s41419-021-04204-7

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Significance of trogocytosis and exosome-mediated transport in establishing and maintaining the tumor microenvironment in lymphoid malignancies2021

    • Author(s)
      Masaharu Kawashima, Hiroshi Higuchi, Ai Kotani
    • Journal Title

      Journal of Clinical and Experimental Hematopathology

      Volume: 61 Issue: 4 Pages: 192-201

    • DOI

      10.3960/jslrt.21005

    • NAID

      130008131967

    • ISSN
      1346-4280, 1880-9952
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Proteomic and phospholipidomic characterization of extracellular vesicles inducing tumor microenvironment in Epstein-Barr virus-associated lymphomas.2021

    • Author(s)
      Ito M, Kudo K, Higuchi H, Otsuka H, Tanaka M, Fukunishi N, Araki T, Takamatsu M, Ino Y, Kimura Y, Kotani A.
    • Journal Title

      FASEB J.

      Volume: 35 Issue: 4

    • DOI

      10.1096/fj.202002730r

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Non-coding RNAs and lipids mediate the function of extracellular vesicles in cancer cross-talk.2021

    • Author(s)
      Kotani A, Ito M, Kudo K.
    • Journal Title

      Semin Cancer Biol.

      Volume: 74 Pages: 121-133

    • DOI

      10.1016/j.semcancer.2021.04.017

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rap1 is essential for B-cell locomotion, germinal center formation and normal B-1a cell population.2021

    • Author(s)
      Ishihara S, Sato T, Sugioka R, Miwa R, Saito H, Sato R, Fukuyama H, Nakajima A, Sawai S, Kotani A, Katagiri K.
    • Journal Title

      Front Immunol.

      Volume: 12 Pages: 624419-624419

    • DOI

      10.3389/fimmu.2021.624419

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression of ERV3-1 in leukocytes of acute myelogenous leukemia patients2021

    • Author(s)
      Nakagawa S, Kawashima M, Miyatake Y, Kudo K, Kotaki R, Ando K, Kotani A.
    • Journal Title

      Gene

      Volume: 773 Pages: 145363-145363

    • DOI

      10.1016/j.gene.2020.145363

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Extracellular vesicles secreted by HBV-infected cells modulate HBV persistence in hydrodynamic HBV transfection mouse model2020

    • Author(s)
      Kakizaki Masatoshi、Yamamoto Yuichiro、Otsuka Motoyuki、Kitamura Kouichi、Ito Masatoshi、Kawai Hideki Derek、Muramatsu Masamichi、Kagawa Tatehiro、Kotani Ai
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 35 Pages: 12449-12460

    • DOI

      10.1074/jbc.ra120.014317

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Overexpression of miR-669m inhibits erythroblast differentiation2020

    • Author(s)
      Kotaki R., et.al. Kawashima M, Yamaguchi A, Suzuki N, Koyama-Nasu R, Ogiya D, Okuyama K, Yamamoto Y, Takamatsu M, Kurosaki N, Ando K, Murata A, Ohtsuka M, Nakagawa S, Katagiri K, Kotani A.
    • Journal Title

      Sci Rep.

      Volume: 10 Issue: 1 Pages: 13554-13554

    • DOI

      10.1038/s41598-020-70442-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PD-L1/L2 protein levels rapidly increase on monocytes via trogocytosis from tumor cells in classical Hodgkin lymphoma2020

    • Author(s)
      Kawashima M, Carreras J, Higuchi H, Kotaki R, Hoshina T, Okuyama K, Suzuki N, Kakizaki M, Miyatake Y, Ando K, Nakayama M, Umezu S, Horie R, Higuchi Y, Katagiri K, Goyama S, Kitamura T, Chamoto K, Yano S,Nakamura N, and A Kotani
    • Journal Title

      Leukemia

      Volume: - Issue: 9 Pages: 2405-2417

    • DOI

      10.1038/s41375-020-0737-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer.2020

    • Author(s)
      Imai Y, Chiba T, Kondo T, Kanzaki H, Kanayama K, Ao J, Kojima R, Kusakabe Y, Nakamura M, Saito T, Nakagawa R, Suzuki E, Nakamoto S, Muroyama R, Tawada A, Matsumura T, Nakagawa T, Kato J, Kotani A, Matsubara H, Kato N.
    • Journal Title

      Oncol Lett

      Volume: 20 Issue: 3 Pages: 2161-2168

    • DOI

      10.3892/ol.2020.11757

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heat-Killed Fusobacterium nucleatum Triggers Varying Heme-Related Inflammatory and Stress Responses Depending on Primary Human Respiratory Epithelial Cell Type.2020

    • Author(s)
      Ryo Koike, Marni E Cueno, Keiko Nodomi, Muneaki Tamura, Noriaki Kamio, Hajime Tanaka, Ai Kotani, Kenichi Imai.
    • Journal Title

      Molecules

      Volume: 25(17) Issue: 17 Pages: 3839-3839

    • DOI

      10.3390/molecules25173839

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PD-L1 is induced on hepatocyte surface via CKLF-like MARVEL transmembrane domain-containing protein 6 upregulation by the anti-HBV drug Entecavir2020

    • Author(s)
      Yamamoto Yuichiro、Kakizaki Masatoshi、Shimizu Takayuki、Carreras Joaquim、Chiba Tetsuhiro、Chamoto Kenji、Kagawa Tatehiro、Aoki Taku、Nakamura Naoya、Ando Kiyoshi、Kotani Ai
    • Journal Title

      International Immunology

      Volume: - Issue: 8 Pages: 519-531

    • DOI

      10.1093/intimm/dxaa018

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dasatinib exacerbates splenomegaly of mice inoculated with Epstein-Barr virus-infected lymphoblastoid cell lines.2020

    • Author(s)
      2)Kotaki R, Kawashima M, Yamamoto Y, Higuchi H, Nagashima E, Kurosaki N, Takamatsu M, Kikuti YY, Imadome KI, Nakamura N, *Kotani A.
    • Journal Title

      Sci Rep.

      Volume: 10(1): Issue: 1 Pages: 4355-4355

    • DOI

      10.1038/s41598-020-61300-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Patent(Industrial Property Rights)] 多価不飽和脂肪酸及び/又はリゾリン脂質を表面に有する細胞外小胞2021

    • Inventor(s)
      幸谷 愛、村上誠、工藤海、中山駿矢
    • Industrial Property Rights Holder
      東海大学 東京大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 劇症型NK白血病に対する治療標的の同定2021

    • Inventor(s)
      幸谷愛、宮竹佑治
    • Industrial Property Rights Holder
      東海大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report

URL: 

Published: 2020-04-28   Modified: 2024-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi