Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity Journal Article
| Authors: | Baatz, F.; Ghosh, A.; Herbst, J.; Polten, S.; Meyer, J.; Rhiel, M.; Maetzig, T.; Geffers, R.; Rothe, M.; Bastone, A. L.; John-Neek, P.; Frühauf, J.; Eiz-Vesper, B.; Bonifacius, A.; Falk, C. S.; Kaisenberg, C. V.; Cathomen, T.; Schambach, A.; van den Brink, M. R. M.; Hust, M.; Sauer, M. G. |
| Article Title: | Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity |
| Abstract: | 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. © 2025 The Authors |
| Keywords: | controlled study; protein expression; leukemia; unclassified drug; genetics; nonhuman; flow cytometry; polymerase chain reaction; cell proliferation; animal cell; mouse; phenotype; animal; cytology; metabolism; animals; mice; animal tissue; cell viability; gene expression; cell maturation; animal experiment; animal model; transcription factor; hematopoietic stem cell transplantation; in vivo study; cell differentiation; cytotoxicity; enzyme linked immunosorbent assay; immunology; immune response; tumor suppressor proteins; western blotting; chimeric antigen receptor; natural killer cell; killer cells, natural; hematopoietic stem cell; tumor suppressor protein; lymphoid progenitor cell; repressor protein; repressor proteins; fluorescence activated cell sorting; therapy; adoptive immunotherapy; immunotherapy, adoptive; peripheral blood mononuclear cell; rna extraction; polyacrylamide gel electrophoresis; coculture; colony forming unit; dna isolation; antileukemic activity; acute myeloid leukemia; lymphoid progenitor cells; lymphoid progenitors; humans; human; female; article; crispr cas system; gene editing; crispr-cas systems; crispr-cas9 system; hek293t cell line; receptors, chimeric antigen; bcl11b; bcl11b protein, human; nk cell differentiation; bcl11 transcription factor b; c1498 cell line |
| Journal Title: | Molecular Therapy |
| Volume: | 33 |
| Issue: | 4 |
| ISSN: | 1525-0016 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-04-02 |
| Start Page: | 1584 |
| End Page: | 1607 |
| Language: | English |
| DOI: | 10.1016/j.ymthe.2025.02.024 |
| PUBMED: | 39955618 |
| PROVIDER: | scopus |
| PMCID: | PMC11997514 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
