Frequent Engagement of the Classical and Alternative NF-kappaB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2007 Aug 19

PMID 17692804

Citations 512

Authors

Christina M Annunziata

R Eric Davis

Yulia Demchenko

William Bellamy

Ana Gabrea

Fenghuang Zhan

Georg Lenz

Ichiro Hanamura

George Wright

Wenming Xiao

Sandeep Dave

Elaine M Hurt

Bruce Tan

Hong Zhao

Owen Stephens

Madhumita Santra

David R Williams

Lenny Dang

Bart Barlogie

John D Shaughnessy Jr

W Michael Kuehl

Louis M Staudt

Affiliations

Soon will be listed here.

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.

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