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bioRxiv · 10.1101/2023.05.06.539691

NF-κB c-REL-OTUD4 axis regulates B-cell receptor in B-cell lymphoma

Katab, E.·Kumar, A. J.·Steiger, K.·Mergner, J.·Azkargorta, M.·Yeroslaviz, A.·Elortza, F.·Fernandez-Saiz, V.
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Abstract

The B-cell receptor (BCR) is essential for B-cell development and a crucial clinical target in immuno-oncology. However, therapeutic success against the BCR and downstream signaling pathways is hampered by enhanced NF-{kappa}B activation as a resistance mechanism. Using a multiomic approach, we discover the c-REL proto-oncogenic subunit of the NF-{kappa}B family as a key transcription factor regulating BCR subunit levels in B-cell lymphoma. Subsequent ChIP- seq, cell biology experiments, and patient data analysis reveal that OTUD4 is a critical deubiquitinase for inhibiting proteasomal degradation of c-REL and for stabilizing a multi-loop positive feedback of NF-{kappa}B to the BCR pathway. Remarkably, OTUD4 downregulation destabilizes c-REL and BCR levels and inhibits cell growth of B cell lymphoma. Thus, we shed light on the malignant potential of c-REL abundance, identify a positive feedback from c-REL to upstream BCR and present OTUD4 as a vulnerability to synergistically target NF-{kappa}B and BCR pathways in B-cell lymphoid malignancies.

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Katab, E., Kumar, A. J., Steiger, K., Mergner, J., Azkargorta, M., Yeroslaviz, A., Elortza, F., Fernandez-Saiz, V.. 2023-05-08. NF-κB c-REL-OTUD4 axis regulates B-cell receptor in B-cell lymphoma. https://doi.org/10.1101/2023.05.06.539691

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