Transcriptomics

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Compensatory IKKa activation of classical NF-kB signaling during IKKb inhibition


ABSTRACT: A subtype of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like (ABC) DLBCL, depends on constitutive NF-kB pathway signaling for survival. Small molecule inhibitors of IkB kinase b (IKKb), a key regulator of the NF-kB pathway, kill ABC DLBCL cells and hold promise for the treatment of this lymphoma type. We conducted an RNA interference genetic screen to investigate potential mechanisms of resistance of ABC DLBCL cells to IKKb inhibitors. We screened a library of small hairpin RNAs (shRNAs) targeting 500 protein kinases for shRNAs that would kill an ABC DLBCL cell line in the presence of a small molecule IKKb inhibitor more effectively than in its absence. Two independent shRNAs targeting IKKa synergized with the IKKb inhibitor to kill three different ABC DLBCL cell lines but were not toxic by themselves. Surprisingly, IKKa shRNAs blocked the classical rather than the alternative NF-kB pathway in ABC DLBCL cells, as judged by inhibition of IkBa phosphorylation. IKKa shRNA toxicity was reversed by coexpression of wild type but not kinase inactive forms of IKKa, suggesting that IKKa may directly phosphorylate IkBa under conditions of IKKb inhibition. These results suggest that therapy for ABC DLBCL may be improved by targeting both IKKa and IKKb. Keywords: compound treatment design Gene expression profiling of OCI-Ly3 cells with or without expressing IKKa shRNA in the presence or absence of 12.5 uM IKKb inhibitor for 2 and 3 days. Four samples were analyzed.

ORGANISM(S): Homo sapiens  

SUBMITTER: Louis M. Staudt  

PROVIDER: E-GEOD-11902 | ArrayExpress | 2009-06-01

SECONDARY ACCESSION(S): GSE11902PRJNA105739

REPOSITORIES: GEO, ArrayExpress

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Publications

Compensatory IKKalpha activation of classical NF-kappaB signaling during IKKbeta inhibition identified by an RNA interference sensitization screen.

Lam Lloyd T LT   Davis R Eric RE   Ngo Vu N VN   Lenz Georg G   Wright George G   Xu Weihong W   Zhao Hong H   Yu Xin X   Dang Lenny L   Staudt Louis M LM  

Proceedings of the National Academy of Sciences of the United States of America 20081222 52


A subtype of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like (ABC) DLBCL, depends on constitutive nuclear factor-kappaB (NF-kappaB) signaling for survival. Small molecule inhibitors of IkappaB kinase beta (IKKbeta), a key regulator of the NF-kappaB pathway, kill ABC DLBCL cells and hold promise for the treatment of this lymphoma type. We conducted an RNA interference genetic screen to investigate potential mechanisms of resistance of ABC DLBCL cells to IKKbeta inhibitors. We  ...[more]

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