title: The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo.
abstract: Research over the past decade has suggested important roles for pseudogenes in physiology and disease. In vitro experiments demonstrated that pseudogenes contribute to cell transformation through several mechanisms. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. Here, we report that mice engineered to overexpress either the full-length murine B-Raf pseudogene Braf-rs1 or its pseudo "CDS" or "3' UTR" develop an aggressive malignancy resembling human diffuse large B cell lymphoma. We show that Braf-rs1 and its human ortholog, BRAFP1, elicit their oncogenic activity, at least in part, as competitive endogenous RNAs (ceRNAs) that elevate BRAF expression and MAPK activation in vitro and in vivo. Notably, we find that transcriptional or genomic aberrations of BRAFP1 occur frequently in multiple human cancers, including B cell lymphomas. Our engineered mouse models demonstrate the oncogenic potential of pseudogenes and indicate that ceRNA-mediated microRNA sequestration may contribute to the development of cancer.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Florian A
authors.initials: FA
authors.lastname: Karreth
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Reschke
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Ruocco
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ng
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Valentine
authors.initials: V
authors.lastname: Léopold
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Marcela
authors.initials: M
authors.lastname: Sjoberg
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Keane
authors.affiliation: Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Verma
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Tay
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wu
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Seitzer
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: Martin Del Castillo
authors.initials: Mdel C
authors.lastname: Velasco-Herrera
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Bothmer
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fung
authors.affiliation: Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Langellotto
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1HH, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Molecular Biotechnology and Health Sciences, University of Torino, 10124 Torino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: ppandolf@bidmc.harvard.edu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D001483:Base Sequence; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D011544:Pseudogenes; D012313:RNA / Q000378:metabolism*
chemical_list: D012313:RNA; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
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