Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. In the activated B cell–like (ABC) subtype of DLBCL, constitutive activation of the nuclear factor κB (NF-κB) pathway prevents apoptosis. In some ABC DLBCLs, a mutation in CARD11 (caspase-associated recruitment domain 11) causes the constitutive activation of NF-κB signaling; however, CARD11 is not mutated in the majority of ABC DLBCLs. To search for other pathways that activate NF-κB in ABC DLBCL cells, Davis et al. performed an RNA interference (RNAi) screen. The survival of ABC DLBCL cell lines with wild-type CARD11, but not those with mutant CARD11, was decreased with transfection of a short hairpin RNA (shRNA) directed against components of the signaling pathway downstream of activated B cell receptors (BCR) such as Bruton’s tyrosine kinase (BTK) and the transmembrane adaptor protein CD79A, which binds to activated BCRs. Total internal reflection microscopy revealed the presence of BCR clusters with limited diffusion on ABC DLBCL cells, similar to those observed on antigen-activated normal B cells. The authors proposed that ABC DLBCLs with wild-type CARD11 depend on “chronic active” BCR signaling for survival. Sequencing of DLBCL cell lines and biopsies from patients with DLBCL identified various mutations in the immunoreceptor tyrosine-based activation motif (ITAM) regions of CD79A and CD79B. The expression of some of these CD79A and CD79B mutants in ABC DLBCL cells resulted in increased BCR surface abundance. ABC DLBCLs with chronic active BCR signaling, but not those that did not require BCR signaling for survival, were sensitive to dasatinib, an inhibitor of Src family kinases and BTK, as well as to the BTK inhibitor PCI-32765. Thus, inhibitors of BCR signaling may be of clinical utility in treating ABC DLBCL.
R. E. Davis, V. N. Ngo, G. Lenz, P. Tolar, R. M. Young, P. B. Romesser, H. Kohlhammer, L. Lamy, H. Zhao, Y. Yang, W. Xu, A. L. Shaffer, G. Wright, W. Xiao, J. Powell, J.-k. Jiang, C. J. Thomas, A. Rosenwald, G. Ott, H. K. Muller-Hermelink, R. D. Gascoyne, J. M. Connors, N. A. Johnson, L. M. Rimsza, E. Campo, E. S. Jaffe, W. H. Wilson, J. Delabie, E. B. Smeland, R. I. Fisher, R. M. Braziel, R. R. Tubbs, J. R. Cook, D. D. Weisenburger, W. C. Chan, S. K. Pierce, L. M. Staudt, Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010). [PubMed]