Analysis of tumor microenvironment in aggressive NK leukemia
| Project/Area Number |
20H03716
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Tokai University |
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Principal Investigator |
Kotani Ai 東海大学, 医学部, 教授 (00517477)
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| 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)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| 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)
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| 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 |
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| 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。
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| 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".
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| 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。
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Report
(4 results)
Research Products
(17 results)
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[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.
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Journal Title
FASEB J.
Volume: 35
Issue: 4
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Front Immunol.
Volume: 12
Pages: 624419-624419
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Sci Rep.
Volume: 10
Issue: 1
Pages: 13554-13554
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Leukemia
Volume: -
Issue: 9
Pages: 2405-2417
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Oncol Lett
Volume: 20
Issue: 3
Pages: 2161-2168
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Sci Rep.
Volume: 10(1):
Issue: 1
Pages: 4355-4355
DOI
Related Report
Peer Reviewed / Open Access
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