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Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice.
Voisset, Edwige; Moravcsik, Eva; Stratford, Eva W; Jaye, Amie; Palgrave, Christopher J; Hills, Robert K; Salomoni, Paolo; Kogan, Scott C; Solomon, Ellen; Grimwade, David.
Afiliación
  • Voisset E; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
  • Moravcsik E; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
  • Stratford EW; Department of Tumor Biology, The Norwegian Radium Hospital/Oslo University Hospital, Oslo, Norway.
  • Jaye A; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
  • Palgrave CJ; School of Veterinary Medicine, University of Surrey, Guildford, United Kingdom.
  • Hills RK; Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University, Cardiff, United Kingdom.
  • Salomoni P; UCL Cancer Institute, London, United Kingdom; and.
  • Kogan SC; Helen Diller Family Comprehensive Cancer Center and.
  • Solomon E; Department of Laboratory Medicine, University of California, San Francisco, CA.
  • Grimwade D; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
Blood ; 131(6): 636-648, 2018 02 08.
Article en En | MEDLINE | ID: mdl-29191918
A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of promyelocytic leukemia (PML) nuclear bodies (NBs) mediated by the PML-retinoic acid receptor α (RARα) oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by 2 point mutations (C62A/C65A) in the Pml RING domain. Although no leukemias developed in PmlC62A/C65A mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period. Additionally, we found that response to targeted therapy with all-trans retinoic acid in vivo was dependent on NB integrity. PML-RARα is recognized to be insufficient for development of APL, requiring acquisition of cooperating mutations. We therefore investigated whether NB disruption might be mutagenic. Compared with wild-type cells, primary PmlC62A/C65A cells exhibited increased sister-chromatid exchange and chromosome abnormalities. Moreover, functional assays showed impaired homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways, with defective localization of Brca1 and Rad51 to sites of DNA damage. These data directly demonstrate that Pml NBs are critical for DNA damage responses, and suggest that Pml NB disruption is a central contributor to APL pathogenesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Promielocítica Aguda / Cuerpos de Inclusión Intranucleares / Reparación del ADN / Proteína de la Leucemia Promielocítica Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Blood Año: 2018 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Promielocítica Aguda / Cuerpos de Inclusión Intranucleares / Reparación del ADN / Proteína de la Leucemia Promielocítica Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Blood Año: 2018 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos