Alternative oncogenic drivers and sensitivity to BTK inhibition in CRISPR/Cas gene-edited human DLBCL cell models.

Authors

Janneke A Eken, Fleur R M Havenaar, Ruben A L de Groen, Edwin Quinten, Hailiang Mei, Julieta H Sepúlveda-Yáñez, Marcelo A Navarrete, Hans G Drexler, Joost S P Vermaat, Cornelis A M van Bergen, Hendrik Veelken

Published in

Blood neoplasia. Volume 3. Issue 3. Pages 100261. Epub Jun 25, 2026.

Abstract

Diffuse large B-cell lymphoma (DLBCL) can be subclassified by phenotype into germinal center B-cell-like and activated B-cell-like (ABC) subtypes and by recurrent potentially oncogenic mutations into 5 to 7 genetic clusters. In ABC-DLBCL, potentially oncogenic mutations frequently occur in genes involved in B-cell receptor (BCR) signaling and NF-κB activation. Autonomous BCR signaling acts as an alternative immunologic driver predominantly in ABC-type DLBCL that cannot be captured by either subclassification system. The relative functional contribution and interdependence of these mechanistically diverse oncogenic drivers have not been completely defined. To directly compare the effects of autonomously signaling BCR and signalosome-activating CARD11 mutations on NF-κB activation and survival of ABC-DLBCL, we reciprocally exchanged these driver mechanisms in the MYD88^L265P-mutated ABC-DLBCL cell lines TMD8 and OCI-Ly3. Only CARD11^L251P (not CARD11^K215N, CARD11^D230N, and CARD11^R337Q) compensated TMD8 cells for the loss of autonomous BCR signaling, as indicated by survival of BCR knockout and conversion to complete resistance to acalabrutinib. Transduction of the TMD8 BCR rescued OCI-Ly3 cells from replacing the CARD11^L215P variant with CARD11^WT. The autonomous TMD8 BCR signal provided a slight growth advantage over CARD11^L251P-driven cells in both reciprocal systems. Unsupervised clustering of genetically engineered TMD8 and OCI-Ly3 clones demonstrated tight clustering with their parental cells and only minor alterations of cellular pathways. Only the strongest signalosome-activating mutation has functional near-equivalency to an autonomously signaling BCR for NF-κB activation and growth and survival in ABC-DLBCL. Quantifying the effects of co-occurring potential NF-κB-activating mechanisms is essential to predict Bruton tyrosine kinase (BTK) inhibition sensitivity in individual ABC-DLBCL cases.

PMID:
42571242
Bibliographic data and abstract were imported from PubMed on 09 Aug 2026.

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