Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype.

Published

Journal Article

Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100's role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.

Full Text

Duke Authors

Cited Authors

  • Guo, X; Koff, JL; Moffitt, AB; Cinar, M; Ramachandiran, S; Chen, Z; Switchenko, JM; Mosunjac, M; Neill, SG; Mann, KP; Bagirov, M; Du, Y; Natkunam, Y; Khoury, HJ; Rossi, MR; Harris, W; Flowers, CR; Lossos, IS; Boise, LH; Dave, SS; Kowalski, J; Bernal-Mizrachi, L

Published Date

  • July 20, 2017

Published In

Volume / Issue

  • 36 / 29

Start / End Page

  • 4224 - 4232

PubMed ID

  • 28368397

Pubmed Central ID

  • 28368397

Electronic International Standard Serial Number (EISSN)

  • 1476-5594

Digital Object Identifier (DOI)

  • 10.1038/onc.2017.90

Language

  • eng

Conference Location

  • England