title: Constitutive canonical NF-κB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma.
abstract: Diffuse large B cell lymphoma (DLBCL) comprises disease entities with distinct genetic profiles, including germinal center B cell (GCB)-like and activated B cell (ABC)-like DLBCLs. Major differences between these two subtypes include genetic aberrations leading to constitutive NF-κB activation and interference with terminal B cell differentiation through BLIMP1 inactivation, observed in ABC- but not GCB-DLBCL. Using conditional gain-of-function and/or loss-of-function mutagenesis in the mouse, we show that constitutive activation of the canonical NF-κB pathway cooperates with disruption of BLIMP1 in the development of a lymphoma that resembles human ABC-DLBCL. Our work suggests that both NF-κB signaling, as an oncogenic event, and BLIMP1, as a tumor suppressor, play causal roles in the pathogenesis of ABC-DLBCL.
authors.affiliation: Children's Hospital, Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dinis Pedro
authors.initials: DP
authors.lastname: Calado
authors.forename: Baochun
authors.initials: B
authors.lastname: Zhang
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Srinivasan
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Jane
authors.initials: J
authors.lastname: Seagal
authors.forename: Christine
authors.initials: C
authors.lastname: Unitt
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.forename: Jeffery
authors.initials: J
authors.lastname: Kutok
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018858:Germinal Center / Q000502:physiology; D051550:I-kappa B Kinase / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010950:Plasma Cells / Q000502:physiology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D016328:NF-kappa B; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse