title: Defective endomitosis during megakaryopoiesis leads to thrombocytopenia in Fanca-/- mice.
abstract: Fanconi anemia (FA) is an inherited chromosomal instability syndrome that is characterized by progressive bone marrow failure. One of the main causes of morbidity and mortality in FA is a bleeding tendency, resulting from low platelet counts. Platelets are the final products of megakaryocyte (MK) maturation. Here, we describe a previously unappreciated role of Fanconi anemia group A protein (Fanca) during the endomitotic process of MK differentiation. Fanca deficiency leads to the accumulation of MKs with low nuclear ploidy and to decreased platelet production. We show, for the first time, that Fanca(-/-) mice are characterized by limited number and proliferative capacity of MK progenitors. Defective megakaryopoiesis of Fanca(-/-) cells is associated with the formation of nucleoplasmic bridges and increased chromosomal instability, indicating that inaccurate endoreplication and karyokinesis occur during MK polyploidization. Sustained DNA damage forces Fanca(-/-) MKs to enter a senescence-like state. Furthermore, inhibition of the Rho-associated kinase, a regulator of cytokinesis, improves the polyploidization of Fanca(-/-) MKs but greatly increases their genomic instability and diminishes their differentiation potential, supporting the notion that accumulation of DNA damage through endomitotic cycles affects MK maturation. Our study indicates that Fanca expression during endomitosis is crucial for normal megakaryopoiesis and platelet production.
authors.affiliation: Université Paris Sud, Orsay, France; Centre national de la recherche scientifique UMR 8200, Institut de Cancérologie Gustave Roussy, Villejuif, France; Equipe Labellisée par La Ligue Contre le Cancer; Institut de Cancérologie Gustave Roussy, Villejuif, France;
authors.forename: Patrycja
authors.initials: P
authors.lastname: Pawlikowska
authors.affiliation: Université Paris Sud, Orsay, France; Commissariat à l'énergie atomique et aux énergies alternatives, Institut de radiobiologie cellulaire et moléculaire, Laboratoire de recherche sur la réparation et la transcription dans les cellules souches, Fontenay-aux-Roses, France; Institut national de la santé et de la recherche médicale U967, Université Paris Diderot, Fontenay-aux-Roses, France; and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouchet
authors.affiliation: Université Paris Sud, Orsay, France; Equipe Labellisée par La Ligue Contre le Cancer; Institut de Cancérologie Gustave Roussy, Villejuif, France; Institut national de la santé et de la recherche médicale UMR 1009, Institut de Cancérologie Gustave Roussy, Villejuif, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Université Paris Sud, Orsay, France; Centre national de la recherche scientifique UMR 8200, Institut de Cancérologie Gustave Roussy, Villejuif, France; Equipe Labellisée par La Ligue Contre le Cancer; Institut de Cancérologie Gustave Roussy, Villejuif, France;
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
authors.affiliation: Université Paris Sud, Orsay, France; Centre national de la recherche scientifique UMR 8200, Institut de Cancérologie Gustave Roussy, Villejuif, France; Equipe Labellisée par La Ligue Contre le Cancer; Institut de Cancérologie Gustave Roussy, Villejuif, France;
authors.forename: Valeria
authors.initials: V
authors.lastname: Naim
mesh_terms: D000818:Animals; D016922:Cellular Senescence / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics; D052217:Fanconi Anemia Complementation Group A Protein / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034061:Thrombopoiesis / Q000235:genetics*
chemical_list: C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein