title: p19 INK4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging.
abstract: Hematopoietic stem cells (HSCs) are characterized by the capacity for self-renewal and the ability to reconstitute the entire hematopoietic compartment. Thrombopoietin maintains adult HSCs in a quiescent state through the induction of cell cycle inhibitors p57(Kip2) and p19(INK4d). Using the p19(INK4d-/-) mouse model, we investigated the role of p19(INK4d) in basal and stress-induced hematopoiesis. We demonstrate that p19(INK4d) is involved in the regulation of HSC quiescence by inhibition of the G0/G1 cell cycle transition. Under genotoxic stress conditions, the absence of p19(INK4d) in HSCs leads to accelerated cell cycle exit, accumulation of DNA double-strand breaks, and apoptosis when cells progress to the S/G2-M stages of the cell cycle. Moreover, p19(INK4d) controls the HSC microenvironment through negative regulation of megakaryopoiesis. Deletion of p19(INK4d) results in megakaryocyte hyperproliferation and increased transforming growth factor β1 secretion. This leads to fibrosis in the bone marrow and spleen, followed by loss of HSCs during aging.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France; University Paris Diderot, 5 rue Thomas-Mann, 75205 Paris, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Hilpert
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Legrand
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France; Ecole Pratique des Hautes Etudes, 4-14 rue Ferrus, 75014 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bluteau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Natalie
authors.initials: N
authors.lastname: Balayn
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Betems
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bluteau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Villeval
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Fawzia
authors.initials: F
authors.lastname: Louache
authors.affiliation: University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gonin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Gilles
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France. Electronic address: hraslova@igr.fr.
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010026:Osteosclerosis / Q000235:genetics / Q000473:pathology; D055728:Primary Myelofibrosis / Q000235:genetics / Q000473:pathology; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D055153:Stem Cell Niche / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D050764:Cyclin-Dependent Kinase Inhibitor p19