title: Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype.
abstract: 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.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Koff
authors.affiliation: Duke Institute for Genome Sciences and Policy, Department of Medicine, Duke University, Durham, NC, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Moffitt
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cinar
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ramachandiran
authors.affiliation: Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Switchenko
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mosunjac
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Neill
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Mann
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bagirov
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, GA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Natkunam
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: Department of Radiation Oncology, Emory University, Atlanta, GA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Rossi
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Harris
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Flowers
authors.affiliation: Division of Hematology Oncology and Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: I S
authors.initials: IS
authors.lastname: Lossos
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Boise
authors.affiliation: Duke Institute for Genome Sciences and Policy, Department of Medicine, Duke University, Durham, NC, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Dave
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.|Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kowalski
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bernal-Mizrachi
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; C489548:NFKB1 protein, human; C498206:NFKB2 protein, human