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Chimeric antigen receptor–induced BCL11B suppression propagates NK-like cell development
Marcel Maluski, … , Marcel R.M. van den Brink, Martin G. Sauer
Marcel Maluski, … , Marcel R.M. van den Brink, Martin G. Sauer
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(12):5108-5122. https://doi.org/10.1172/JCI126350.
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Research Article Immunology Article has an altmetric score of 30

Chimeric antigen receptor–induced BCL11B suppression propagates NK-like cell development

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Abstract

The transcription factor B cell CLL/lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here, we show that chimeric antigen receptor (CAR) expression during early phases of ex vivo generation of lymphoid progenitors suppressed BCL11B, leading to suppression of T cell–associated gene expression and acquisition of NK cell–like properties. Upon adoptive transfer into hematopoietic stem cell transplant recipients, CAR-expressing lymphoid progenitors differentiated into CAR-induced killer (CARiK) cells that mediated potent antigen-directed antileukemic activity even across MHC barriers. CD28 and active immunoreceptor tyrosine–based activation motifs were critical for a functional CARiK phenotype. These results give important insights into differentiation of murine and human lymphoid progenitors driven by synthetic CAR transgene expression and encourage further evaluation of ex vivo–generated CARiK cells for targeted immunotherapy.

Authors

Marcel Maluski, Arnab Ghosh, Jessica Herbst, Vanessa Scholl, Rolf Baumann, Jochen Huehn, Robert Geffers, Johann Meyer, Holger Maul, Britta Eiz-Vesper, Andreas Krueger, Axel Schambach, Marcel R.M. van den Brink, Martin G. Sauer

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Figure 3

im1928z1 expression on HSPCs leads to BCL11B suppression, allowing for CARiK cell development, and concomitantly decreases T cell–associated gene expression.

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im1928z1 expression on HSPCs leads to BCL11B suppression, allowing for C...
(A) For microarray data analysis, RNA from Tom+-sorted im1928z1-generated lymphoid progenitors (n = 3) or iTom‑engineered lymphoid progenitors (n = 3) immediately previous to cotransplantation or from spleen-derived progeny (n = 2, respectively) were isolated on day 28 after transplantation. (B) PCA of total transcriptome profiles from either engineered lymphoid progenitors or their respective progeny is graphed. (C) Volcano plot for comparison of differently regulated transcripts in im1928z1-generated lymphoid progenitors and iTom controls. Gene symbols in the boxes indicate selected transcripts found to be downregulated (green) or upregulated (red) at least 2-fold (P < 0.05) in im1928z1-generated lymphoid progenitors as compared with controls. (D) Recombination of D and J regions of the TCRβ locus in engineered lymphoid progenitors. Genomic DNA of engineered progenitors was isolated on day 20 of culture, and rearrangements were detected by PCR. Splenocytes and thymocytes from WT B6 mice were used as controls. Results from 1 of 2 independent experiments are shown. GL, germ line band. (E) Heatmap showing the relative expression of transcripts for selected TFs. Data are normalized according to expression in each row. (F) NOTCH1 expression on transgene-positive (Tom+) or transgene-negative (Tom–) lymphoid progenitors engineered with im1928z1. Student’s t test was used. Data represent mean ± SEM. **P < 0.01. (G) Western blot analysis for BCL11B in lysates from iTom lymphoid progenitors, im1928z1-generated lymphoid progenitors, or B6 WT thymocytes. Representative data from 1 of 2 independent experiments are shown. (H) Relative expression of selected transcripts for NK cell receptors, integrins, adaptors, effector molecules, and TFs in engineered lymphoid progenitors and their progeny. Data are normalized according to expression in each row.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 6 patents
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