A brain organoid/ALL coculture model reveals the AP-1 pathway as critically associated with CNS involvement of BCP-ALL.

IF 7.4 1区 医学 Q1 HEMATOLOGY Blood advances Pub Date : 2024-10-08 DOI:10.1182/bloodadvances.2023011145
Philip Gebing, Stefanos Loizou, Sebastian Hänsch, Julian Schliehe-Diecks, Lea Spory, Pawel Stachura, Vera H Jepsen, Melina Vogt, Aleksandra A Pandyra, Herui Wang, Zhengping Zhuang, Johannes Zimmermann, Martin Schrappe, Gunnar Cario, Ameera Alsadeq, Denis M Schewe, Arndt Borkhardt, Lennart Lenk, Ute Fischer, Sanil Bhatia
{"title":"A brain organoid/ALL coculture model reveals the AP-1 pathway as critically associated with CNS involvement of BCP-ALL.","authors":"Philip Gebing, Stefanos Loizou, Sebastian Hänsch, Julian Schliehe-Diecks, Lea Spory, Pawel Stachura, Vera H Jepsen, Melina Vogt, Aleksandra A Pandyra, Herui Wang, Zhengping Zhuang, Johannes Zimmermann, Martin Schrappe, Gunnar Cario, Ameera Alsadeq, Denis M Schewe, Arndt Borkhardt, Lennart Lenk, Ute Fischer, Sanil Bhatia","doi":"10.1182/bloodadvances.2023011145","DOIUrl":null,"url":null,"abstract":"<p><strong>Abstract: </strong>Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The disease mechanisms of CNS leukemia are primarily investigated using 2-dimensional cell culture and mouse models. Given the variations in cellular identity and architecture between the human and murine CNS, it becomes imperative to seek complementary models to study CNS leukemia. Here, we present a first-of-its-kind 3-dimensional coculture model combining human brain organoids and BCP-ALL cells. We noticed significantly higher engraftment of BCP-ALL cell lines and patient-derived xenograft (PDX) cells in cerebral organoids than non-ALL cells. To validate translatability between organoid coculture and in vivo murine models, we confirmed that targeting CNS leukemia-relevant pathways such as CD79a/Igα or C-X-C motif chemokine receptor 4-stromal cell-derived factor 1 reduced the invasion of BCP-ALL cells into organoids. RNA sequencing and functional validations of organoid-invading leukemia cells compared with the noninvaded fraction revealed significant upregulation of activator protein 1 (AP-1) transcription factor-complex members in organoid-invading cells. Moreover, we detected a significant enrichment of AP-1 pathway genes in PDX ALL cells recovered from the CNS compared with spleen blasts of mice that had received transplantation with TCF3::PBX1+ PDX cells, substantiating the role of AP-1 signaling in CNS disease. Accordingly, we found significantly higher levels of the AP-1 gene, jun proto-oncogene, in patients initially diagnosed as CNS-positive BCP-ALL compared with CNS-negative cases as well as CNS-relapse vs non-CNS-relapse cases in a cohort of 100 patients with BCP-ALL. Our results suggest CNS organoids as a novel model to investigate CNS involvement and identify the AP-1 pathway as a critical driver of CNS disease in BCP-ALL.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465051/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood advances","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1182/bloodadvances.2023011145","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Abstract: Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The disease mechanisms of CNS leukemia are primarily investigated using 2-dimensional cell culture and mouse models. Given the variations in cellular identity and architecture between the human and murine CNS, it becomes imperative to seek complementary models to study CNS leukemia. Here, we present a first-of-its-kind 3-dimensional coculture model combining human brain organoids and BCP-ALL cells. We noticed significantly higher engraftment of BCP-ALL cell lines and patient-derived xenograft (PDX) cells in cerebral organoids than non-ALL cells. To validate translatability between organoid coculture and in vivo murine models, we confirmed that targeting CNS leukemia-relevant pathways such as CD79a/Igα or C-X-C motif chemokine receptor 4-stromal cell-derived factor 1 reduced the invasion of BCP-ALL cells into organoids. RNA sequencing and functional validations of organoid-invading leukemia cells compared with the noninvaded fraction revealed significant upregulation of activator protein 1 (AP-1) transcription factor-complex members in organoid-invading cells. Moreover, we detected a significant enrichment of AP-1 pathway genes in PDX ALL cells recovered from the CNS compared with spleen blasts of mice that had received transplantation with TCF3::PBX1+ PDX cells, substantiating the role of AP-1 signaling in CNS disease. Accordingly, we found significantly higher levels of the AP-1 gene, jun proto-oncogene, in patients initially diagnosed as CNS-positive BCP-ALL compared with CNS-negative cases as well as CNS-relapse vs non-CNS-relapse cases in a cohort of 100 patients with BCP-ALL. Our results suggest CNS organoids as a novel model to investigate CNS involvement and identify the AP-1 pathway as a critical driver of CNS disease in BCP-ALL.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
脑有机体/ALL 共培养模型揭示了 AP-1 通路与 BCP-ALL 的中枢神经系统受累密切相关。
中枢神经系统(CNS)受累仍然是治疗儿童 B 细胞前体急性淋巴细胞白血病(BCP-ALL)的临床障碍。中枢神经系统白血病的发病机制主要通过二维细胞培养和小鼠模型进行研究。鉴于人类和小鼠中枢神经系统的细胞特征和结构存在差异,因此必须寻找互补模型来研究中枢神经系统白血病。在这里,我们首次提出了一种结合人脑器官组织和 BCP-ALL 细胞的三维共培养模型。我们注意到,与非ALL细胞相比,BCP-ALL细胞系和患者异种移植(PDX)细胞在脑器官组织中的接种率明显更高。为了验证类器官共培养与体内小鼠模型之间的可转化性,我们证实靶向中枢神经系统白血病相关通路(如 CD79a/Igα 或 CXCR4-SDF1)可减少 BCP-ALL 细胞对类器官的侵袭。与未被侵入的细胞相比,对侵入类器官的白血病细胞进行RNA测序和功能验证后发现,在侵入类器官的细胞中,AP-1转录因子复合物成员显著上调。此外,与移植了TCF3::PBX1+ PDX细胞的小鼠脾脏囊泡相比,我们发现从中枢神经系统回收的ALL-PDX细胞中AP-1通路基因明显丰富,这证实了AP-1信号在中枢神经系统疾病中的作用。因此,我们在一组 100 名 BCP-ALL 患者中发现,最初诊断为 CNS 阳性的患者与 CNS 阴性的患者相比,以及 CNS 复发与非 CNS 复发的患者相比,AP-1 基因 JUN 的水平明显更高。我们的研究结果表明,中枢神经系统器质性病变是研究中枢神经系统参与的一种新型模型,并确定 AP-1 通路是 BCP-ALL 中枢神经系统疾病的关键驱动因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Blood advances
Blood advances Medicine-Hematology
CiteScore
12.70
自引率
2.70%
发文量
840
期刊介绍: Blood Advances, a semimonthly medical journal published by the American Society of Hematology, marks the first addition to the Blood family in 70 years. This peer-reviewed, online-only, open-access journal was launched under the leadership of founding editor-in-chief Robert Negrin, MD, from Stanford University Medical Center in Stanford, CA, with its inaugural issue released on November 29, 2016. Blood Advances serves as an international platform for original articles detailing basic laboratory, translational, and clinical investigations in hematology. The journal comprehensively covers all aspects of hematology, including disorders of leukocytes (both benign and malignant), erythrocytes, platelets, hemostatic mechanisms, vascular biology, immunology, and hematologic oncology. Each article undergoes a rigorous peer-review process, with selection based on the originality of the findings, the high quality of the work presented, and the clarity of the presentation.
期刊最新文献
Selective Btk inhibition by PRN1008/PRN473 blocks human CLEC-2, and PRN473 reduces venous thrombosis formation in mice. Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma. Cardiac events after allo-HCT in patients with acute myeloid leukemia. Consensus recommendations for severe aplastic anemia. Genetic variants in canonical Wnt signaling pathway associated with pediatric immune thrombocytopenia.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1