{"id":"hum0116","version":2,"url":"https://humandbs.dbcls.jp/research/hum0116/v2","datePublished":"2025-12-04","versions":[{"version":1,"datePublished":"2020-11-20"},{"version":2,"datePublished":"2025-12-04"}],"title":{"ja":"ヒト化マウス（humanized mouse） の作製と免疫学研究への応用","en":"Development of hunanized mice for human immunity research"},"summary":{"aims":{"ja":"本研究の目的は、マウスモデルからヒト疾患への応用のギャップを埋めることである。ヒト造血幹細胞およびヒト疾患由来幹細胞を免疫不全マウスに移植することで、ヒトの病態を再現するモデルを作製し、\n・ヒト急性骨髄性白血病（acute myelogenous leukemia：AML）関連遺伝子変異を同定する。\n・AMLとキメラ抗原受容体（CAR）T細胞療法の開発に焦点を当て、ケモカイン受容体CXCR4の強制発現が、CAR-T細胞の記憶獲得と長期的持続性を促進し、白血病に対する治療効果および耐久性を高めることを明らかにする。","en":"This study aims to bridge the gap between mouse models and human disease. To this end, we identified somatic mutations associated with human acute myelogenous leukemia (AML) pathogenesis using leukemia cells derived from human leukemia stem cells and from patient-derived xenograft (PDX) mice, which recapitulate human disease by transplanting leukemia stem cells into immunodeficient mice. Furthermore, focusing on AML and the development of chimeric antigen receptor (CAR) T-cell therapy, we investigated how enforced expression of the chemokine receptor CXCR4 promotes memory acquisition and long-term persistence of CAR-T cells, thereby enhancing both the therapeutic efficacy and durability against leukemia."},"methods":{"ja":"Target Captureシークエンシング（Acute Myeloid Leukemia Cancer Panel、ならびに、41遺伝子）、シングルセルRNAシークエンシング","en":"Target Capture sequencing (Acute Myeloid Leukemia Cancer Panel and 41 genes), single cell RNA sequencing"},"targets":{"ja":"【Target Capture】 AML症例より採取した白血病幹細胞、ならびに、白血病幹細胞を輸注した免疫不全マウスの内、白血病を発症したヒト化マウスから採取したヒト白血病細胞\n【scRNA-seq】純化したAML1症例の白血病細胞を移植した10匹のPDXマウスより収集したヒト臍帯血由来CAR-T細胞（CXCR4強制発現あり/なし）およびAML患者由来白血病細胞","en":"Leukemia stem cells from AML patients or humanized mice with leukemia derived from immune deficiency mice which were infused with human leukemia stem cells, human cord blood-derived CAR-T cells (with or without CXCR4 overexpression) injected into AML patient-derived xenograft (PDX) mice and collected from liver, spleen, and bone marrow, and patient-derived AML blasts"},"url":{"ja":[{"url":"https://www.riken.jp/research/labs/ims/hum_dis_model/","text":"https://www.riken.jp/research/labs/ims/hum_dis_model/"}],"en":[{"url":"https://www.riken.jp/en/research/labs/ims/hum_dis_model/","text":"https://www.riken.jp/en/research/labs/ims/hum_dis_model/"}]}},"listingSummary":{"methods":{"ja":"配列決定\n発現","en":"Sequencing, Expression profiling"},"targets":{"ja":"急性骨髄性白血病：118＋1症例\n（日本人）","en":"118 + 1 AMLs\n(Japanese)"},"typeOfData":{"ja":"NGS\n（Target Capture、scRNA-seq）","en":"NGS\n(Target Capture, scRNA-seq)"}},"releaseNote":{"ja":"急性骨髄性白血病（AML）1症例の純化した白血病細胞を移植して10匹のPDXマウスを作製後、健常ドナー5名の臍帯血由来CAR-T細胞（CXCR4強制発現あり/なし：計10種）をそれぞれ投与し、2.5週間後（肝臓・脾臓；CAR-T細胞およびAML）、4週間もしくは5ヶ月後（骨髄；CAR-T細胞のみ）に収集した各組織それぞれからセルソータにて純化した健常ドナー由来のCART-T細胞およびAML症例由来の白血病細胞から取得したRNAを用いたsingle cell RNAseqデータをfastqファイルにて提供する。","en":"Purified AML blasts from n=1 patient were engrafted into recipient mice to generate PDX (n=10). PDX were infused with CAR-T cells derived from cord blood of five healthy donors (with or without enforced CXCR4 expression; 10 total conditions). CAR-T cells of healthy-donor origin and leukemia cells of patient origin were purified 2.5 weeks (liver, spleen; CAR-T cells and AML blasts) and at either 4 weeks or 5 months (bone marrow; CAR-T cells only) by cell sorting. Single-cell RNA-seq data generated from the sorted cells (FASTQ files) are provided as part of this submission."},"dataProviders":[{"name":{"ja":"石川 文彦","en":"Fumihiko Ishikawa"},"organization":{"name":{"ja":"理化学研究所統合生命医科学センター・ヒト疾患モデル研究チーム","en":"Laboratory for Human Disease Models, Riken Center for Integrative Medical Sciences"}}}],"researchProjects":[{"name":{"ja":"白血病再発克服プロジェクト","en":"Target AML project"},"url":{"ja":null,"en":null}}],"grants":[],"relatedPublications":[{"title":"Overcoming mutational complexity in acute myeloid leukemia by inhibition of critical pathways","doi":"https://doi.org/10.1126/scitranslmed.aao1214","datasets":["JGAD000133"]},{"title":"Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive Acute Myeloid Leukemia","doi":"https://doi.org/10.1038/s43018-021-00177-w","datasets":["JGAD000355"]},{"title":"CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting","doi":"https://doi.org/10.1038/s41467-025-67745-x","datasets":["JGAD000990"]}],"datasets":["JGAD000133","JGAD000355","JGAD000990"],"controlledAccessUsers":[{"principalInvestigator":{"ja":"浜田 道昭","en":"Michiaki Hamada"},"affiliation":{"ja":"浜田研究室, 理工学術院, 早稲田大学","en":"Hamada Laboratory, Faculty of Science and Engineering, Waseda University"},"country":{"ja":"日本","en":"Japan"},"researchTitle":{"ja":"RNA標的創薬データベースの構築","en":"Construction of RNA-targeted Drug Discovery Database"},"periodStart":"2023-01-05","periodEnd":"2027-10-31","datasets":["JGAD000133","JGAD000355","JGAD000990"]}]}