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Cited by 1,643

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma

Open access
Davis, R. Eric, Ngo, Vu N., Lenz, Georg, Tolar, Pavel, Young, Ryan M., Romesser, Paul B., Kohlhammer, Holger, Lamy, Laurence, Zhao, Hong, Yang, Yandan, Xu, Weihong, Shaffer, Arthur L., Wright, George, Xiao, Wenming, Powell, John, Jiang, Jian-kang, Thomas, Craig J., Rosenwald, Andreas, Ott, German, Muller-Hermelink, Hans Konrad, Gascoyne, Randy D., Connors, Joseph M., Johnson, Nathalie A., Rimsza, Lisa M., Campo, Elias, Jaffe, Elaine S., Wilson, Wyndham H., Delabie, Jan, Smeland, Erlend B., Fisher, Richard I., Braziel, Rita M., Tubbs, Raymond R., Cook, J. R., Weisenburger, Dennis D., Chan, Wing C., Pierce, Susan K., Staudt, Louis M.·2010·Nature
DOI 10.1038/nature08638
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Abstract

A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of ‘chronic active’ BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-κB pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-κB, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton’s tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-κ, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt’s lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.

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Authors
Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., Xu, W., Shaffer, A. L., Wright, G., Xiao, W., Powell, J., Jiang, J.-K., Thomas, C. J., Rosenwald, A., Ott, G., Muller-Hermelink, H. K., Gascoyne, R. D., Connors, J. M., Johnson, N. A., Rimsza, L. M., Campo, E., Jaffe, E. S., Wilson, W. H., Delabie, J., Smeland, E. B., Fisher, R. I., Braziel, R. M., Tubbs, R. R., Cook, J. R., Weisenburger, D. D., Chan, W. C., Pierce, S. K., & Staudt, L. M.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2010-01
Volume
463
Issue
7277
Pages
88-92
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature08638
OpenAlex
W1979816280
Cited by
1,643
References
4
FWCI
59.42
Type
journal article
Language
en
Open access
green

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