Eric Davis and colleagues provide a rational basis for developing new types of therapies for diffuse large B-cell lymphoma (DLBCL) patients not responding well to chemotherapy.
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.
Histology and microarray images from patients with germinal-centre B-like diffuse large B-cell lymphoma (left) versus activated B-like diffuse large B-cell lymphoma. Courtesy of Louis Staudt, National Cancer Institute, Bethesda, Maryland, USA.
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-B 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-B capable of binding its target sequences were present in ABC-DLBCL lines, but not in GC-DLBCL lines.
NF-B is activated by degradation of its inhibitory subunit, IB. The signal that sends IB for destruction is phosphorylation by IB 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 IB in ABC-DLBCL cells plummeted, whereas IB in GC-DLBCL cells was much more stable. So NF-B seems to be activated in ABC-DLBCL cells through the classical IKK pathway.
The authors then tried to block NF-B signalling by introducing a 'super-repressor' mutant of IB 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-B signalling pathway for survival. Likewise, a dominant-negative mutant of IKK 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-B 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.
Cath Brooksbank
References
ORIGINAL RESEARCH PAPER Davis, R. E. et al. Constitutive NF-B activity is required for survival of activated B-like diffuse large B-cell lymphoma cells. J. Exp. Med.194, 1861–1874 (2001) | PubMed |
FURTHER READING Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature403, 503–511 (2000) | Article | PubMed |
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B 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-
