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A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma
https://repo.qst.go.jp/records/81901
https://repo.qst.go.jp/records/81901d07ea723-e7a2-4c40-9653-e2365daf92f6
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2021-02-19 | |||||
| タイトル | ||||||
| タイトル | A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Kensuke, Tateishi
× Kensuke, Tateishi× Miyake , Yohei× Kawazu , Masahito× Sasaki, Nobuyoshi× Nakamura, Taishi× Sasame, Jo× Yukie, Yoshii× Ueno, Toshihide× Miyake, Akio× Watanabe, Jun× Matsushita, Yuko× Shiba, Norio× Udaka, Naoko× Ohki, Kentaro× L Fink, Alexandria× S Tummala, Shilpa× Natsumeda, Manabu× Ikegaya, Naoki× Nishi, Mayuko× Ohtake, Makoto× Ryohei Miyazaki× Suenaga, Jun× Murata, Hidetoshi× Ichio, Aoki× J Miller, Julie× Yukihiko Fujii× Ryo, Akihide× Yamanaka, Shoji× Mano, Hiroyuki× P Cahill, Daniel× Hiroaki Wakimoto× S Chi, Andrew× Tracy T Batchelor× Nagane, Motoo× Ichimura, Koichi× Yamamoto, Tetsuya× Yukie, Yoshii× Ichio, Aoki |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. SIGNIFICANCE: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5330/F1.large.jpg. | |||||
| 書誌情報 |
Cancer Research 巻 80, 号 23, p. 5330-5343, 発行日 2020-12 |
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| 出版者 | ||||||
| 出版者 | AACR | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 0008-5472 | |||||
| PubMed番号 | ||||||
| 識別子タイプ | PMID | |||||
| 関連識別子 | 33067267 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1158/0008-5472.CAN-20-2425 | |||||
| 関連サイト | ||||||
| 識別子タイプ | URI | |||||
| 関連識別子 | https://cancerres.aacrjournals.org/content/80/23/5330 | |||||
