Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL
Janneke A. Eken, Marvyn T. Koning, Kristýna Kupcová, Julieta Sepúlveda-Yáñez, Ruben A. L. de Groen, Edwin Quinten, Jurriaan Janssen, Cornelis A.M. van Bergen, Joost S.P. Vermaat, Arjen H.G. Cleven, Marcelo A. Navarrete, Bauke Ylstra, Daphne de Jong, Ondřej Havránek, Hassan Jumaa, Hendrik Veelken
Abstract
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.