Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL

Eken, Janneke A.; Koning, Marvyn T.; Kupcova, Kristyna; Yanez, Julieta H. Sepulveda; de Groen, Ruben A. L.; Quinten, Edwin; Janssen, Jurriaan; van Bergen, Cornelis A. M.; Vermaat, Joost S. P.; Cleven, Arjen; Navarrete Signorile, Marcelo Alejandro; Ylstra, Bauke; de Jong, Daphne; Havranek, Ondrej; Jumaa, Hassan; Veelken, Hendrik

doi:10.1084/jem.20230941

Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL

Eken, Janneke A.

[1];

Koning, Marvyn T.

[1];

Kupcova, Kristyna

[2];

Yanez, Julieta H. Sepulveda

[1];

de Groen, Ruben A. L.

[1];

Quinten, Edwin

[1];

Janssen, Jurriaan

[3];

van Bergen, Cornelis A. M.

[1];

Vermaat, Joost S. P.

[1];

Cleven, Arjen

[4];

Navarrete Signorile, Marcelo Alejandro

[5];

Ylstra, Bauke

[3];

de Jong, Daphne

[3];

Havranek, Ondrej

[2];

Jumaa, Hassan

[6];

Veelken, Hendrik

[1]

¹
Leiden University
²
Charles University Prague
³
Amsterdam Univ Med Ctr
⁴
Leiden University - Excl LUMC
⁵
Escuela de Medicina
⁶
Ulm University

DOI

10.1084/jem.20230941

Date Issued

2024-3-21

Type

Artículo

Journal

Journal of Experimental Medicine

ISSN

0022-1007

1540-9538

Open Access

hybrid

Volume

221

Links

https://arca.umag.cl/handle/123456789/14728

This study describes and characterizes antigen-independent, autonomous signaling of the clonal B cell receptor as an intrinsic oncogenic driver in activated B cell type DLBCL. This long-sought non-genetic lymphomagenic mechanism has profound implications for development of effective novel therapies. 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-kappa B 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.

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