A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation
| Autor: | William Vainchenker, Caroline Marty, Rodolphe Besancenot, Stéphane Giraudier, Yann Lécluse, Ronan Chaligne, Florence Pasquier, Carole Tonetti, Stefan N. Constantinescu |
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| Přispěvatelé: | Bases fondamentales et stratégies nouvelles en cancérologie (BFSNC - IFR54), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hematopoïese et cellules souches normales et pathologiques (U790), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Ludwig Institute for Cancer Research, This work was supported by grants from the INSERM and la Ligue Nationale contre le Cancer. Funding to SNC was from Fondation Salus Sanguinis, the Action de Recherche Concertée (ARC) MEXP31C1 of the Université catholique de Louvain, the Fondation contre le cancer, the Atlantic Philanthropies, New York, the PAI Program BCHM61B5, Belgium and the Fonds National de la Recherche Scientifique (FNRS), Belgium, UCL - Instituts de recherche et pôles (publication post 2010), Autard, Delphine |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Senescence
MAPK/ERK pathway QH301-705.5 Hematology/Hematopoiesis Megakaryocyte differentiation Cellular differentiation MESH: Cell Cycle Biology General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences 0302 clinical medicine MESH: Cell Proliferation [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Biology (General) Cellular Senescence Thrombopoietin Cell Proliferation 030304 developmental biology 0303 health sciences MESH: Humans General Immunology and Microbiology Cell growth General Neuroscience Cell Cycle food and beverages Cell cycle MESH: Thrombopoietin Cell biology MESH: Cell Line MESH: Megakaryocytes MESH: Cell Aging Cell Aging Hematology/Myeloproliferative Disorders including Chronic Myeloid Leukemia 030220 oncology & carcinogenesis General Agricultural and Biological Sciences Megakaryocytes Cell aging Research Article |
| Zdroj: | PLoS Biology PLoS Biology, Public Library of Science, 2010, 8 (9), epub ahead of print. ⟨10.1371/journal.pbio.1000476⟩ PLoS Biology, 2010, 8 (9), epub ahead of print. ⟨10.1371/journal.pbio.1000476⟩ PLoS Biology, Vol. 8, no.9, p. 0 (2010) PLoS Biology, Vol 8, Iss 9 (2010) |
| ISSN: | 1544-9173 1545-7885 |
| DOI: | 10.1371/journal.pbio.1000476⟩ |
| Popis: | During normal megakaryocyte development, in response to thrombopoetin, mature cells enter a senescence-like state in which they shed platelets; this state, characterized by cell cycle arrest, is defective in malignant megakaryocytes. Thrombopoietin (TPO) via signaling through its cognate receptor MPL is a key cytokine involved in the regulation of megakaryocyte differentiation leading to platelet production. Mature megakaryocytes are polyploid cells that have arrested DNA replication and cellular proliferation but continue sustained protein synthesis. Here, we show that TPO induces cell-cycle arrest in the megakaryocytic UT7-MPL cell line by the activation of the ERK/MAPK pathway, induction of p21CIP transcription, and senescence markers through EGR1 activation. A similar senescence-like process was also detected in normal primary postmitotic megakaryocytes. In contrast, senescence was not observed in malignant megakaryocytes derived from primary myelofibrosis patients (a form of chronic myeloid hemopathy). Our data indicate that polyploid mature megakaryocytes receive signals from TPO to arrest cell proliferation and enter a senescent-like state. An escape from this physiological process may be associated with certain myeloproliferative neoplasms leading to abnormal megakaryocytic proliferation. Author Summary Megakaryocytes are huge bone marrow cells that shed platelets into the blood stream to promote clotting at sites of injury. Mature megakaryocytes differentiate from precursor cells in response to a hormone called thrombopoetin. Here, we show that as part of this normal differentiation process mature megakaryocytes enter a state called senescence in which cell division stops—a feature normally associated with cell aging and death. By studying megakaryocytes in culture, we were able to determine the biochemical pathway induced by thrombopoetin that leads to gene activation associated with senescence. We conclude that thrombopoietin acts differently at two steps in megakaryocyte differentiation: in the early stages it induces megakaryocyte proliferation, and at a latter stage it arrests the cell division cycle leading to platelet production by these cells. Interestingly, certain malignant megakaryocytes did not undergo senescence in response to thrombopoetin, which might explain the abnormal proliferation of these cancerous cells. |
| Databáze: | OpenAIRE |
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