A Senescence-Like Cell-Cycle Arrest Occurs During Megakaryocytic Maturation: Implications for Physiological and Pathological Megakaryocytic Proliferation

• DOI: 10.1371/journal.pbio.1000476
• Publication Date: 2010-09-07T20:26:29Z
• Authors: Rodolphe Besancenot; Ronan Chaligné; Carole Tonetti; Florence Pasquier; Caroline Marty; Yann Lécluse; William Vainchenker; Stefan N. Constan...; Stéphane Giraudier
• Keywords: 0301 basic medicine; MESH: Humans; QH301-705.5; Cell Cycle; MESH: Cell Cycle; MESH: Thrombopoietin; MESH: Cell Line; Cell Line; MESH: Megakaryocytes; 03 medical and health sciences; MESH: Cell Aging; Thrombopoietin; Cell Aging; MESH: Cell Proliferation; [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology; Humans; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; Biology (General); Megakaryocytes; Cellular Senescence; Research Article; Cell Proliferation

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.