title: Loss of PRDM11 promotes MYC-driven lymphomagenesis.
abstract: The PR-domain (PRDM) family of genes encodes transcriptional regulators, several of which are deregulated in cancer. By using a functional screening approach, we sought to identify novel tumor suppressors among the PRDMs. Here we demonstrate oncogenic collaboration between depletion of the previously uncharacterized PR-domain family member Prdm11 and overexpression of MYC. Overexpression of PRDM11 inhibits proliferation and induces apoptosis. Prdm11 knockout mice are viable, and loss of Prdm11 accelerates MYC-driven lymphomagenesis in the Eµ-Myc mouse model. Moreover, we show that patients with PRDM11-deficient diffuse large B-cell lymphomas (DLBCLs) have poorer overall survival and belong to the nongerminal center B-cell-like subtype. Mechanistically, genome-wide mapping of PRDM11 binding sites coupled with transcriptome sequencing in human DLBCL cells evidenced that PRDM11 associates with transcriptional start sites of target genes and regulates important oncogenes such as FOS and JUN. Hence, we characterize PRDM11 as a putative novel tumor suppressor that controls the expression of key oncogenes, and we add new mechanistic insight into B-cell lymphomagenesis.
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Cathrine Kolster
authors.initials: CK
authors.lastname: Fog
authors.affiliation: Department of Hematology.
authors.forename: Fazila
authors.initials: F
authors.lastname: Asmar
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Christophe
authors.initials: C
authors.lastname: Côme
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Klaus Thorleif
authors.initials: KT
authors.lastname: Jensen
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Jens Vilstrup
authors.initials: JV
authors.lastname: Johansen
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Tony Bou
authors.initials: TB
authors.lastname: Kheir
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Linda
authors.initials: L
authors.lastname: Jacobsen
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Carsten
authors.initials: C
authors.lastname: Friis
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Alison
authors.initials: A
authors.lastname: Louw
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Louise
authors.initials: L
authors.lastname: Rosgaard
authors.affiliation: Department of Clinical Immunology, and.
authors.forename: Nina Friesgaard
authors.initials: NF
authors.lastname: Øbro
authors.affiliation: Department of Clinical Immunology, and.
authors.forename: Hanne Vibeke
authors.initials: HV
authors.lastname: Marquart
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;
authors.forename: Kristian
authors.initials: K
authors.lastname: Anthonsen
authors.affiliation: Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands; and.
authors.forename: Arie Koen
authors.initials: AK
authors.lastname: Braat
authors.affiliation: Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands; and.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
authors.affiliation: Department of Pathology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ralfkiaer
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark; Department of Hematology.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Grønbæk
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Anders Henrik
authors.identifier: http://orcid.org/0000-0002-7407-3398
authors.initials: AH
authors.lastname: Lund
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C489428:Myc protein, mouse; C000588732:PRDM11 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins