Franziska Baatz, Arnab Ghosh, Jessica Herbst, Saskia Polten, Johann Meyer, Manuel Rhiel, Tobias Maetzig, Robert Geffers, Michael Rothe, Antonella Lucia Bastone, Philipp John-Neek, Jörg Frühauf, Britta Eiz-Vesper, Agnes Bonifacius, Christine S Falk, Constantin V Kaisenberg, Toni Cathomen, Axel Schambach, Marcel R M van den Brink, Michael Hust, Martin G Sauer
{"title":"靶向BCL11B在car工程淋巴样祖细胞驱动nk样细胞发育具有持久的抗白血病活性。","authors":"Franziska Baatz, Arnab Ghosh, Jessica Herbst, Saskia Polten, Johann Meyer, Manuel Rhiel, Tobias Maetzig, Robert Geffers, Michael Rothe, Antonella Lucia Bastone, Philipp John-Neek, Jörg Frühauf, Britta Eiz-Vesper, Agnes Bonifacius, Christine S Falk, Constantin V Kaisenberg, Toni Cathomen, Axel Schambach, Marcel R M van den Brink, Michael Hust, Martin G Sauer","doi":"10.1016/j.ymthe.2025.02.024","DOIUrl":null,"url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-induced suppression of the transcription factor B cell CLL/lymphoma 11B (BCL11B) propagates CAR-induced killer (CARiK) cell development from lymphoid progenitors. Here, we show that CRISPR-Cas9-mediated Bcl11b knockout in human and murine early lymphoid progenitors distinctively modulates this process either alone or in combination with a CAR. Upon adoptive transfer into hematopoietic stem cell recipients, Bcl11b-edited progenitors mediated innate-like antigen-independent anti-leukemic immune responses. With CAR expression allowing for additional antigen-specific responses, the progeny of double-edited lymphoid progenitors acquired prolonged anti-leukemic activity in vivo. These findings give important insights into how Bcl11b targeting can be used to tailor anti-leukemia functionality of CAR-engineered lymphoid progenitor cells.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1584-1607"},"PeriodicalIF":12.1000,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity.\",\"authors\":\"Franziska Baatz, Arnab Ghosh, Jessica Herbst, Saskia Polten, Johann Meyer, Manuel Rhiel, Tobias Maetzig, Robert Geffers, Michael Rothe, Antonella Lucia Bastone, Philipp John-Neek, Jörg Frühauf, Britta Eiz-Vesper, Agnes Bonifacius, Christine S Falk, Constantin V Kaisenberg, Toni Cathomen, Axel Schambach, Marcel R M van den Brink, Michael Hust, Martin G Sauer\",\"doi\":\"10.1016/j.ymthe.2025.02.024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Chimeric antigen receptor (CAR)-induced suppression of the transcription factor B cell CLL/lymphoma 11B (BCL11B) propagates CAR-induced killer (CARiK) cell development from lymphoid progenitors. Here, we show that CRISPR-Cas9-mediated Bcl11b knockout in human and murine early lymphoid progenitors distinctively modulates this process either alone or in combination with a CAR. Upon adoptive transfer into hematopoietic stem cell recipients, Bcl11b-edited progenitors mediated innate-like antigen-independent anti-leukemic immune responses. With CAR expression allowing for additional antigen-specific responses, the progeny of double-edited lymphoid progenitors acquired prolonged anti-leukemic activity in vivo. These findings give important insights into how Bcl11b targeting can be used to tailor anti-leukemia functionality of CAR-engineered lymphoid progenitor cells.</p>\",\"PeriodicalId\":19020,\"journal\":{\"name\":\"Molecular Therapy\",\"volume\":\" \",\"pages\":\"1584-1607\"},\"PeriodicalIF\":12.1000,\"publicationDate\":\"2025-04-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ymthe.2025.02.024\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/15 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2025.02.024","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity.
Chimeric antigen receptor (CAR)-induced suppression of the transcription factor B cell CLL/lymphoma 11B (BCL11B) propagates CAR-induced killer (CARiK) cell development from lymphoid progenitors. Here, we show that CRISPR-Cas9-mediated Bcl11b knockout in human and murine early lymphoid progenitors distinctively modulates this process either alone or in combination with a CAR. Upon adoptive transfer into hematopoietic stem cell recipients, Bcl11b-edited progenitors mediated innate-like antigen-independent anti-leukemic immune responses. With CAR expression allowing for additional antigen-specific responses, the progeny of double-edited lymphoid progenitors acquired prolonged anti-leukemic activity in vivo. These findings give important insights into how Bcl11b targeting can be used to tailor anti-leukemia functionality of CAR-engineered lymphoid progenitor cells.
期刊介绍：
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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