The Journal of experimental medicine · 2024
Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL.
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Eken Janneke A, Koning Marvyn T, Kupcova Kristyna, Sepúlveda Yáñez Julieta H, de Groen Ruben A L, Quinten Edwin, Janssen Jurriaan, van Bergen Cornelis A M, Vermaat Joost S P, Cleven Arjen, Navarrete Marcelo A, Ylstra Bauke, de Jong Daphne, Havranek Ondrej, Jumaa Hassan, Veelken Hendrik
Аннотация
Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.