{"created":"2023-05-15T15:00:20.927637+00:00","id":81901,"links":{},"metadata":{"_buckets":{"deposit":"768640af-525b-48bc-ac36-4d50a9fcd060"},"_deposit":{"created_by":1,"id":"81901","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"81901"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00081901","sets":["1"]},"author_link":["1012338","1012357","1012362","1012356","1012368","1012353","1012347","1012364","1012371","1012337","1012348","1012361","1012366","1012336","1012350","1012354","1012365","1012335","1012360","1012369","1012343","1012342","1012359","1012339","1012352","1012334","1012349","1012355","1012363","1012351","1012370","1012340","1012358","1012346","1012367","1012341","1012344","1012345"],"item_8_biblio_info_7":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2020-12","bibliographicIssueDateType":"Issued"},"bibliographicIssueNumber":"23","bibliographicPageEnd":"5343","bibliographicPageStart":"5330","bibliographicVolumeNumber":"80","bibliographic_titles":[{"bibliographic_title":"Cancer Research"}]}]},"item_8_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"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. ","subitem_description_type":"Abstract"}]},"item_8_publisher_8":{"attribute_name":"出版者","attribute_value_mlt":[{"subitem_publisher":"AACR"}]},"item_8_relation_13":{"attribute_name":"PubMed番号","attribute_value_mlt":[{"subitem_relation_type_id":{"subitem_relation_type_id_text":"33067267","subitem_relation_type_select":"PMID"}}]},"item_8_relation_14":{"attribute_name":"DOI","attribute_value_mlt":[{"subitem_relation_type_id":{"subitem_relation_type_id_text":"10.1158/0008-5472.CAN-20-2425","subitem_relation_type_select":"DOI"}}]},"item_8_relation_17":{"attribute_name":"関連サイト","attribute_value_mlt":[{"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://cancerres.aacrjournals.org/content/80/23/5330","subitem_relation_type_select":"URI"}}]},"item_8_source_id_9":{"attribute_name":"ISSN","attribute_value_mlt":[{"subitem_source_identifier":"0008-5472","subitem_source_identifier_type":"ISSN"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"metadata 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Jo"}],"nameIdentifiers":[{"nameIdentifier":"1012339","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Yukie, Yoshii"}],"nameIdentifiers":[{"nameIdentifier":"1012340","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ueno, Toshihide"}],"nameIdentifiers":[{"nameIdentifier":"1012341","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Miyake, Akio"}],"nameIdentifiers":[{"nameIdentifier":"1012342","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Watanabe, Jun"}],"nameIdentifiers":[{"nameIdentifier":"1012343","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Matsushita, Yuko"}],"nameIdentifiers":[{"nameIdentifier":"1012344","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Shiba, Norio"}],"nameIdentifiers":[{"nameIdentifier":"1012345","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Udaka, Naoko"}],"nameIdentifiers":[{"nameIdentifier":"1012346","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ohki, Kentaro"}],"nameIdentifiers":[{"nameIdentifier":"1012347","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"L Fink, Alexandria"}],"nameIdentifiers":[{"nameIdentifier":"1012348","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"S Tummala, Shilpa"}],"nameIdentifiers":[{"nameIdentifier":"1012349","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Natsumeda, Manabu"}],"nameIdentifiers":[{"nameIdentifier":"1012350","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ikegaya, Naoki"}],"nameIdentifiers":[{"nameIdentifier":"1012351","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Nishi, Mayuko"}],"nameIdentifiers":[{"nameIdentifier":"1012352","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ohtake, Makoto"}],"nameIdentifiers":[{"nameIdentifier":"1012353","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ryohei Miyazaki"}],"nameIdentifiers":[{"nameIdentifier":"1012354","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Suenaga, Jun"}],"nameIdentifiers":[{"nameIdentifier":"1012355","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Murata, Hidetoshi"}],"nameIdentifiers":[{"nameIdentifier":"1012356","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ichio, Aoki"}],"nameIdentifiers":[{"nameIdentifier":"1012357","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"J Miller, Julie"}],"nameIdentifiers":[{"nameIdentifier":"1012358","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Yukihiko Fujii"}],"nameIdentifiers":[{"nameIdentifier":"1012359","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ryo, Akihide"}],"nameIdentifiers":[{"nameIdentifier":"1012360","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Yamanaka, Shoji"}],"nameIdentifiers":[{"nameIdentifier":"1012361","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Mano, Hiroyuki"}],"nameIdentifiers":[{"nameIdentifier":"1012362","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"P Cahill, Daniel"}],"nameIdentifiers":[{"nameIdentifier":"1012363","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Hiroaki Wakimoto"}],"nameIdentifiers":[{"nameIdentifier":"1012364","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"S Chi, Andrew"}],"nameIdentifiers":[{"nameIdentifier":"1012365","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Tracy T Batchelor"}],"nameIdentifiers":[{"nameIdentifier":"1012366","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Nagane, Motoo"}],"nameIdentifiers":[{"nameIdentifier":"1012367","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ichimura, Koichi"}],"nameIdentifiers":[{"nameIdentifier":"1012368","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Yamamoto, Tetsuya"}],"nameIdentifiers":[{"nameIdentifier":"1012369","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Yukie, Yoshii","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1012370","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ichio, Aoki","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1012371","nameIdentifierScheme":"WEKO"}]}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"journal article","resourceuri":"http://purl.org/coar/resource_type/c_6501"}]},"item_title":"A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma"}]},"item_type_id":"8","owner":"1","path":["1"],"pubdate":{"attribute_name":"公開日","attribute_value":"2021-02-19"},"publish_date":"2021-02-19","publish_status":"0","recid":"81901","relation_version_is_last":true,"title":["A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T18:56:17.152653+00:00"}