Davis RE, Ngo VN, Lenz G, et al. . Nature. 2010;463:88-92.
Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma
 

The existence of two subtypes of diffuse large B-cell lymphoma (DLBL) emerged as an observation from gene expression profiling studies a decade ago,1  but the underlying biology of the difference is still being explored. The initial observation was that DLBL could be separated into at least two main types based on patterns of gene expression: germinal center (GCB) and activated B-cell (ABC). Among previous findings was that a minority of ABC cases have mutations in the CARD-11 gene, an important component of the signalling pathway upstream of NFκB, which is known to be constitutively active in ABC DLBL.2  It was not, however, known how the activation was sustained in the 90 percent of cases with wild-type CARD-11.

This paper, from the same multicenter collaborative group led by Louis Staudt from NCI as the original observation, takes as its starting point the observation in an interference screen that short hairpin RNAs (shRNAs) directed against Bruton tyrosine kinase (BTK) were lethal to ABC cell lines, but only those with wild-type CARD-11. BTK is a component of the signalling cascade downstream of the B-cell receptor (BCR). The authors went on to explore other aspects of BCR signalling and found that shRNAs against CD79A, CD79B, IgM, and Ig-k could all exert selective killing against ABC lines with wild-type CARD-11, accompanied by reduced phosphorylation of the signalling intermediaries such as Akt, ERK, and IkB-α. Most significantly, they found mutations in the activation motif of CD79B in ABC lines and a significant minority of ABC DLBL biopsies (26 out of 161) while only 2/64 GCB showed such changes. They showed that in CD79B mutant cells the BCR complexes in the cell membrane tended to form relatively immobile clusters, as are seen in antigen-stimulated normal B-cells, and that the activity of the BCR signalling inhibitory Lyn kinase was reduced.

These data suggest that in ABC DLBL, mutations in BCR components, such as CD79B, may be responsible for abnormal retention of the BCR on the cell membrane following stimulation. This can lead to activation of potentially important pathogenic pathways, in particular NF-κB. This may provide an explanation for the origins of some ABC DLBL and suggests possible therapeutic targets in the BCR and its signalling pathways. The authors examined the effects of dasatinib and other inhibitors of BTK and showed some selective killing of wild-type CARD-11 ABC lines, as distinct from the more general effects of IKK-β inhibitors, which killed all ABC lines.

There is growing recognition that the subtypes of DLBL appear to pursue different clinical courses, with GCB having a substantially better outlook than ABC, at least when the classification is made on gene expression at the mRNA level.3  There is, therefore, particular interest in understanding the biology of the ABC type, in order to develop more rational strategies to improve the results of treatment. This paper takes us another step in that direction, with the insight that anomalies of BCR signalling may be particularly important, especially early in pathogenesis when the abnormal prolongation of a physiologic signal may provide the basis for malignant transformation. It is not clear whether specific inhibitors of these pathways will be more useful than drugs that may act further downstream, such as proteosome or mTOR inhibitors, but this can at least be tested.

1.
Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503-11.
2.
Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319:1676-79.
3.
Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359:2313-23.

Competing Interests

Dr. Johnson receives research funding from Janssen-Cilag.