Mol Ther. 2025 Feb 15:S1525-0016(25)00114-5. doi: 10.1016/j.ymthe.2025.02.024. Online ahead of print.
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.
PMID:39955618 | DOI:10.1016/j.ymthe.2025.02.024
