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CARD11 gain of function upregulates BCL2A1 and promotes resistance to targeted therapies combination in B-cell lymphoma [scRNA-seq]

GSE239497 Homo sapiens Expression profiling by high throughput sequencing 7 samples Submitted 2025/12/01 Platform GPL24676
Summary
Strategy combining targeted therapies is effective in B-cell lymphomas such as mantle celllymphoma (MCL), but acquired resistances remain a recurrent issue. Herein, we performed integrative longitudinal genomic and single-cell RNA-seq analyses of MCL patients treated with targeted therapies against CD20, BCL2 and BTK (i.e., OAsIs trial). We revealed the emergence of subclones with a selective advantage against OAsIs combination in vivo and showed that resistant cells were characterized by BCR-independent overexpression of NFkB1 target genes, especially due to CARD11 mutations. Functional studies demonstrated that CARD11 gain of function not only resulted in BCR independence, but also directly increase the transcription of the antiapoptotic BCL2A1, leading to venetoclax and OAsIs combination resistance. Based on the transcriptional profile of OAsIs-resistant subclones, we designed a 16-gene resistance signature that was also predictive for MCL patients treated with conventional chemotherapy, underlying a common escape mechanism.
Published in
CARD11 gain of function upregulates BCL2A1 expression and promotes resistance to targeted therapies combination in B-cell lymphoma
Decombis S, Bellanger C, Le Bris Y et al. · Blood 2023 · PMID 37562004 · doi:10.1182/blood.2023020211
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Also filed as BioProject PRJNA999589 and SRA study SRP453980. Searching any of these in the dataset finder brings you back here.

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