title: Frequent engagement of RelB activation is critical for cell survival in multiple myeloma.
abstract: The NF-κB family of transcription factors has emerged as a key player in the pathogenesis of multiple myeloma (MM). NF-κB is activated by at least two major signaling pathways. The classical pathway results in the activation of mainly RelA containing dimers, whereas the alternative pathway leads to the activation of RelB/p52 and RelB/p50 heterodimers. Activating mutations in regulators of the alternative pathway have been identified in 17% of MM patients. However, the status of RelB activation per se and its role in the regulation of cell survival in MM has not been investigated. Here, we reveal that 40% of newly diagnosed MM patients have a constitutive RelB DNA-binding activity in CD138(+) tumor cells, and we show an association with increased expression of a subset of anti-apoptotic NF-κB target genes, such as cIAP2. Furthermore, we demonstrate that RelB exerts a crucial anti-apoptotic activity in MM cells. Our findings indicate that RelB activation is key for promoting MM cell survival through the upregulation of anti-apoptotic proteins. Altogether, our study provides the framework for the development of new molecules targeting RelB in the treatment of MM.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Cormier
authors.forename: Hélène
authors.initials: H
authors.lastname: Monjanel
authors.forename: Claire
authors.initials: C
authors.lastname: Fabre
authors.forename: Katy
authors.initials: K
authors.lastname: Billot
authors.forename: Elène
authors.initials: E
authors.lastname: Sapharikas
authors.forename: Fanny
authors.initials: F
authors.lastname: Chereau
authors.forename: Didier
authors.initials: D
authors.lastname: Bordereaux
authors.forename: Thierry J
authors.initials: TJ
authors.lastname: Molina
authors.forename: Hervé
authors.initials: H
authors.lastname: Avet-Loiseau
authors.forename: Véronique
authors.initials: V
authors.lastname: Baud
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D015398:Signal Transduction; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D051841:Transcription Factor RelB / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases
chemical_list: D051034:Inhibitor of Apoptosis Proteins; C498143:RELA protein, human; C497593:RELB protein, human; C508241:SDC1 protein, human; D053668:Syndecan-1; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D004247:DNA; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases
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