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Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.

ABSTRACT: Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta) targeting the classical NF-kappaB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-kappaB pathway is frequent in myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease.

SUBMITTER: Annunziata CM

PROVIDER: S-EPMC2730509 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.

Annunziata Christina M CM Davis R Eric RE Demchenko Yulia Y Bellamy William W Gabrea Ana A Zhan Fenghuang F Lenz Georg G Hanamura Ichiro I Wright George G Xiao Wenming W Dave Sandeep S Hurt Elaine M EM Tan Bruce B Zhao Hong H Stephens Owen O Santra Madhumita M Williams David R DR Dang Lenny L Barlogie Bart B Shaughnessy John D JD Kuehl W Michael WM Staudt Louis M LM

Cancer cell 20070801 2

Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta) targeting the classical NF-kappaB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell ...[more]

PMID: 17692804

Dataset Information

Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.

Publications

Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.

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