title: NR4A1-mediated apoptosis suppresses lymphomagenesis and is associated with a favorable cancer-specific survival in patients with aggressive B-cell lymphomas.
abstract: NR4A1 (Nur77) and NR4A3 (Nor-1) function as tumor suppressor genes as demonstrated by the rapid development of acute myeloid leukemia in the NR4A1 and NR4A3 knockout mouse. The aim of our study was to investigate NR4A1 and NR4A3 expression and function in lymphoid malignancies. We found a vastly reduced expression of NR4A1 and NR4A3 in chronic lymphocytic B-cell leukemia (71%), in follicular lymphoma (FL, 70%), and in diffuse large B-cell lymphoma (DLBCL, 74%). In aggressive lymphomas (DLBCL and FL grade 3), low NR4A1 expression was significantly associated with a non-germinal center B-cell subtype and with poor overall survival. To investigate the function of NR4A1 in lymphomas, we overexpressed NR4A1 in several lymphoma cell lines. Overexpression of NR4A1 led to a higher proportion of lymphoma cells undergoing apoptosis. To test the tumor suppressor function of NR4A1 in vivo, the stable lentiviral-transduced SuDHL4 lymphoma cell line harboring an inducible NR4A1 construct was further investigated in xenografts. Induction of NR4A1 abrogated tumor growth in the NSG mice, in contrast to vector controls, which formed massive tumors. Our data suggest that NR4A1 has proapoptotic functions in aggressive lymphoma cells and define NR4A1 as a novel gene with tumor suppressor properties involved in lymphomagenesis.
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Alexander J A
authors.initials: AJ
authors.lastname: Deutsch
authors.forename: Beate
authors.initials: B
authors.lastname: Rinner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wenzl
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.forename: Katharina
authors.initials: K
authors.lastname: Troppan
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steinbauer
authors.forename: Daniela
authors.initials: D
authors.lastname: Schwarzenbacher
authors.forename: Sonja
authors.initials: S
authors.lastname: Reitter
authors.forename: Julia
authors.initials: J
authors.lastname: Feichtinger
authors.forename: Sascha
authors.initials: S
authors.lastname: Tierling
authors.forename: Andreas
authors.initials: A
authors.lastname: Prokesch
authors.forename: Marcel
authors.initials: M
authors.lastname: Scheideler
authors.forename: Anne
authors.initials: A
authors.lastname: Krogsdam
authors.forename: Gerhard G
authors.initials: GG
authors.lastname: Thallinger
authors.forename: Helmut
authors.initials: H
authors.lastname: Schaider
authors.forename: Christine
authors.initials: C
authors.lastname: Beham-Schmid
authors.forename: Peter
authors.initials: P
authors.lastname: Neumeister
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000401:mortality*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D016016:Proportional Hazards Models; D011987:Receptors, Steroid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C490412:NR4A3 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone