MCM8-and MCM9 Deficiencies Cause Lifelong Increased Hematopoietic DNA Damage Driving p53- Dependent Myeloid Tumors
Autor: | Jean-Sébastien Hoffmann, Marie Tosolini, Cindy da Costa de Jesus, Malik Lutzmann, Caroline Marty, Dana Hodroj, Candice Marchive, Marcel Méchali, Caroline Bret, William Vainchenker, Isabelle Plo, Luc Forichon, Florence Bernex, Sophie Queille |
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Přispěvatelé: | Lutzmann, Malik, Unraveling the code of DNA replication origins and its link with cell identity - ORICODE - - EC:FP7:ERC2009-02-01 - 2014-01-31 - 233339 - VALID, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Our research received funding from the INCA-Cancero- pole Emergence program and from the European Research Council (FP7/ 2007-2013, grant agreement 233339),as well as from Laboratoire d’Excellence Toulouse-Cancer (TOUCAN). This work was also supported by Agence Nationale de la Recherche (ANR), Fondation ARC pour la Recherche sur le Cancer, Ligue Nationale Contre le Cancer (LNCC), and Ligue Régionale Contre le Cancer Haute Garonne., European Project: 233339,EC:FP7:ERC,ERC-2008-AdG,ORICODE(2009), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), BioCampus Montpellier (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Bordeaux (UB), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE12-0011,2R-POL,ADN polymérase theta : lien entre réplication et réparation de l'ADN(2016) |
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Aging Myeloid DNA damage DNA repair Apoptosis homologous recombination [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] medicine.disease_cause Retinoblastoma Protein General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Bone Marrow medicine [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] Animals cancer MCM8 lcsh:QH301-705.5 MCM9 Cell Proliferation Mice Knockout Minichromosome Maintenance Proteins Gene Expression Regulation Leukemic business.industry Myelodysplastic syndromes Cell Differentiation Cell cycle medicine.disease hematopoiesis 3. Good health myelodysplastic syndrome Haematopoiesis 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) Hematologic Neoplasms Splenomegaly Cancer research Bone marrow Tumor Suppressor Protein p53 Carcinogenesis business 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | Cell Reports Cell Reports, 2019, 28 (11), pp.2851-2865. ⟨10.1016/j.celrep.2019.07.095⟩ Cell Reports, Elsevier Inc, 2019, 28 (11), pp.2851-2865. ⟨10.1016/j.celrep.2019.07.095⟩ Cell Reports, Vol 28, Iss 11, Pp 2851-2865.e4 (2019) |
ISSN: | 2211-1247 |
Popis: | Summary: Hematopoiesis is particularly sensitive to DNA damage. Myeloid tumor incidence increases in patients with DNA repair defects and after chemotherapy. It is not known why hematopoietic cells are highly vulnerable to DNA damage. Addressing this question is complicated by the paucity of mouse models of hematopoietic malignancies due to defective DNA repair. We show that DNA repair-deficient Mcm8- and Mcm9-knockout mice develop myeloid tumors, phenocopying prevalent myelodysplastic syndromes. We demonstrate that these tumors are preceded by a lifelong DNA damage burden in bone marrow and that they acquire proliferative capacity by suppressing signaling of the tumor suppressor and cell cycle controller RB, as often seen in patients. Finally, we found that absence of MCM9 and the tumor suppressor Tp53 switches tumorigenesis to lymphoid tumors without precedent myeloid malignancy. Our results demonstrate that MCM8/9 deficiency drives myeloid tumor development and establishes a DNA damage burdened mouse model for hematopoietic malignancies. : Lutzmann et al. show that MCM8- or MCM9-deficient mice suffer chronic DNA damage, causing myeloid tumors, resembling human myelodysplastic syndromes, during aging. These tumors lose RB-mediated cell cycle control, cause splenomegaly, and preclude progressively normal hematopoiesis. Additional loss of the tumor suppressor Tp53 switches tumor development to T cell lymphoma. Keywords: MCM8, MCM9, DNA damage, DNA repair, myelodysplastic syndrome, cancer, homologous recombination, hematopoiesis |
Databáze: | OpenAIRE |
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