title: Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia.
abstract: To explore how RUNX1 mutations predispose to leukemia, we generated induced pluripotent stem cells (iPSCs) from 2 pedigrees with germline RUNX1 mutations. The first, carrying a missense R174Q mutation, which acts as a dominant-negative mutant, is associated with thrombocytopenia and leukemia, and the second, carrying a monoallelic gene deletion inducing a haploinsufficiency, presents only as thrombocytopenia. Hematopoietic differentiation of these iPSC clones demonstrated profound defects in erythropoiesis and megakaryopoiesis and deregulated expression of RUNX1 targets. iPSC clones from patients with the R174Q mutation specifically generated an increased amount of granulomonocytes, a phenotype reproduced by an 80% RUNX1 knockdown in the H9 human embryonic stem cell line, and a genomic instability. This phenotype, found only with a lower dosage of RUNX1, may account for development of leukemia in patients. Altogether, RUNX1 dosage could explain the differential phenotype according to RUNX1 mutations, with a haploinsufficiency leading to thrombocytopenia alone in a majority of cases whereas a more complete gene deletion predisposes to leukemia.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Hématologie Biologique, Université Paris-Est Créteil, Hôpital Henri Mondor, Créteil, France; Université Paris Diderot, Paris, France;
authors.forename: Iléana
authors.initials: I
authors.lastname: Antony-Debré
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Diderot, Paris, France;
authors.forename: Vladimir T
authors.initials: VT
authors.lastname: Manchev
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Balayn
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France; Ecole Pratique des Hautes Etudes, Paris, France;
authors.forename: Dominique
authors.initials: D
authors.lastname: Bluteau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France; Centre Hospitalier Universitaire de Poitiers, Service d'Oncologie Hématologique et Thérapie Cellulaire, Poitiers, France;
authors.forename: Cécile
authors.initials: C
authors.lastname: Tomowiak
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France;
authors.forename: Céline
authors.initials: C
authors.lastname: Legrand
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Langlois
authors.affiliation: Gustave Roussy, Villejuif, France;
authors.forename: Olivia
authors.initials: O
authors.lastname: Bawa
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U935-Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris Service d'Histologie Embryologie et Cytogénétique, Clamart, France;
authors.forename: Lucie
authors.initials: L
authors.lastname: Tosca
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U935-Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris Service d'Histologie Embryologie et Cytogénétique, Clamart, France;
authors.forename: Gérard
authors.initials: G
authors.lastname: Tachdjian
authors.affiliation: Centre Hospitalier Universitaire de Nancy, Pôle Enfant, Service de Médecine Infantile et de Génétique Clinique, Vandoeuvre-Les-Nancy, France; Faculté de Médecine, Université de Lorraine, Vandoeuvre-Les-Nancy, France;
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France;
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.affiliation: Department of Pathology and Laboratory Medicine, and.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Mills
authors.affiliation: Department of Pathology and Laboratory Medicine, and.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: French
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Service d'Hématologie Biologique, Paris, France.
authors.forename: Remi
authors.initials: R
authors.lastname: Favier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France;
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France; Gustave Roussy, Villejuif, France; Université Paris Sud, Villejuif, France;
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006410:Hematopoiesis; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D013921:Thrombocytopenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human