Why do patients with diffuse large B-cell lymphoma (DLBCL) — the most common form of non-Hodgkin's lymphoma — have such a variable response to chemotherapy? Eric Davis and colleagues now provide a rational basis for developing new types of therapies for the poor responders.
Microarray studies indicate that there are two types of DLBCL, one resembling resting, germinal-centre B cells (GC-DLBCL), the other, which responds poorly to standard chemotherapy, with characteristics of activated B cells (ABC-DLBCL). Analysis of these published results revealed that several genes in the NF-κB pathway are highly expressed in ABC-DLBCL, but not in GC-DLBCL. The same was true of cell lines derived from the two DLBCL types, and band-shift assays showed that high levels of NF-κB capable of binding its target sequences were present in ABC-DLBCL lines, but not in GC-DLBCL lines.
NF-κB is activated by degradation of its inhibitory subunit, IκB. The signal that sends IκB for destruction is phosphorylation by IκB kinase (IKK). Is this pathway operative in ABC-DLBCL? In vitro kinase asays revealed that IKK from ABC-DLBCL cell lines, but not from GC-DLBCL cell lines, was constitutively active and, when protein synthesis was blocked, levels of IκB in ABC-DLBCL cells plummeted, whereas IκB in GC-DLBCL cells was much more stable. So NF-κB seems to be activated in ABC-DLBCL cells through the classical IKK pathway.
The authors then tried to block NF-κB signalling by introducing a 'super-repressor' mutant of IαB that cannot be phosphorylated by IKK. The super-repressor was toxic to ABC-DLBCL cells but had no effect on the survival of GC-DLBCL cells. So, ABC-DLBCL cells seem to rely on their constitutively active NF-κB signalling pathway for survival. Likewise, a dominant-negative mutant of IKKβ was also selectively toxic to ABC-DLBCL cells.
This mechanistic difference between the two types of DLBCL not only indicates why ABC-DLBCL might be more resistant to chemotherapy than the GC type, but also suggests a means of tackling that resistance. Drugs that block the NF-κB pathway are already in clinical trials, so it should not be long before these observations are put to the most important test of all — in DLBCL patients.
References
ORIGINAL RESEARCH PAPER
Davis, R. E. et al. Constitutive NF-κB activity is required for survival of activated B-like diffuse large B-cell lymphoma cells. J. Exp. Med. 194, 1861–1874 (2001)
FURTHER READING
Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000)
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Brooksbank, C. From microarray to mechanism. Nat Rev Cancer 2, 9 (2002). https://doi.org/10.1038/nrc717
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DOI: https://doi.org/10.1038/nrc717