Biology subjects

Langouet, M.

Publications and source records attributed to Langouet, M..

2 recordsLinked to original sources

bioRxiv2025

CD33 Epitope Editing Unlocks UM171-Expanded Cord Blood Grafts for AML Immunotherapy

Immunotherapies in acute myeloid leukemia (AML) are limited by shared antigen expression between leukemic and healthy hematopoietic cells, leading to on-target toxicity. Here we developed a clinically scalable strategy to engineer cord blood (CB)-derived hematopoietic stem and progenitor cell (HSPC) grafts resistant to CD33-directed therapies. Leveraging UM171-mediated expansion and adenine base editing, we precisely disrupted a critical epitope in CD33 required for gemtuzumab ozogamicin (GO) binding, centered on phenylalanine 21, while preserving CD33 expression and its sialic acid binding function. Ex vivo edited HSPCs maintained robust multilineage engraftment, T-cell output, and conferred protection from GO-induced myelotoxicity in xenograft models, without impairing anti-leukemic efficacy. Editing was efficient across multiple donors, enriched in primitive subsets, and exhibited minimal off-target activity by ultra-deep exome sequencing. Our work establishes base editor-driven epitope engineering as an improved approach to CD33-targeted immunotherapy-compatible HSPC grafts, enabling safe integration of currently available agents into post-transplant care.

immunology↗

bioRxiv2020

Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons

Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS iPSCs. However, ZNF274 has many other targets in the genome in addition to SNORD116. Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared to ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116. These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS.

genetics↗