title: Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia.
abstract: In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012 Paris, France.|AP-HP, Hôpital St Antoine, Service d'Hématologie clinique et de thérapie cellulaire, F-75012 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hirsch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 1170, CNRS GDR 3697 Micronit, 94805 Villejuif, France.|Institut Gustave Roussy, Univ Paris-Sud, Université Paris Saclay, 94805 Villejuif, France.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: AP-HP, Hôpital St Antoine, Service d'Hématologie clinique et de thérapie cellulaire, F-75012 Paris, France.
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 1170, CNRS GDR 3697 Micronit, 94805 Villejuif, France.|Institut Gustave Roussy, Univ Paris-Sud, Université Paris Saclay, 94805 Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Joulin
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012 Paris, France.|Department of Pediatric Hematology and Oncology, AP-HP, Hôpital Armand-Trousseau, F-75012 Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Boutroux
authors.affiliation: Institut Gustave Roussy, Univ Paris-Sud, Université Paris Saclay, 94805 Villejuif, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Pronier
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012 Paris, France.
authors.forename: Hannah
authors.initials: H
authors.lastname: Moatti
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012 Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Flandrin
authors.affiliation: AP-HP, Hôpital Saint-Antoine &Hôpital Armand-Trousseau, Service d'hématologie biologique, F-75012 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marzac
authors.affiliation: AP-HP, Hôpital Henri Mondor, Unité d'Hématologie Moléculaire, F-94010 Créteil, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bories
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Fava
authors.affiliation: Institut Gustave Roussy, Univ Paris-Sud, Université Paris Saclay, 94805 Villejuif, France.
authors.forename: Hayat
authors.initials: H
authors.lastname: Mokrani
authors.affiliation: Institut Gustave Roussy, Univ Paris-Sud, Université Paris Saclay, 94805 Villejuif, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Betems
authors.affiliation: AP-HP, Hôpital Saint-Antoine, Laboratoire commun de biologie et génétique moléculaires, F-75012 Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Lorre
authors.affiliation: AP-HP, Hôpital Saint-Antoine &Hôpital Armand-Trousseau, Service d'hématologie biologique, F-75012 Paris, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Favier
authors.affiliation: AP-HP, Hôpital Saint-Antoine &Hôpital Armand-Trousseau, Service d'hématologie biologique, F-75012 Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Féger
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012 Paris, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mohty
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|AP-HP, Hôpital Saint-Antoine &Hôpital Armand-Trousseau, Service d'hématologie biologique, F-75012 Paris, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Douay
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012 Paris, France.|AP-HP, Hôpital St Antoine, Service d'Hématologie clinique et de thérapie cellulaire, F-75012 Paris, France.
authors.forename: Ollivier
authors.initials: O
authors.lastname: Legrand
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012 Paris, France.|AP-HP, Hôpital Saint-Antoine &Hôpital Armand-Trousseau, Service d'hématologie biologique, F-75012 Paris, France.
authors.forename: Chrystèle
authors.initials: C
authors.lastname: Bilhou-Nabera
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 1170, CNRS GDR 3697 Micronit, 94805 Villejuif, France.|Institut Gustave Roussy, Univ Paris-Sud, Université Paris Saclay, 94805 Villejuif, France.
authors.forename: Fawzia
authors.identifier: http://orcid.org/0000-0002-4247-5421
authors.initials: F
authors.lastname: Louache
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, F-75012 Paris, France.|AP-HP, Hôpital Saint-Antoine &Hôpital Armand-Trousseau, Service d'hématologie biologique, F-75012 Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Delhommeau
mesh_terms: D000818:Animals; D001483:Base Sequence; D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells; D044127:Epigenesis, Genetic; D015321:Gene Rearrangement / Q000235:genetics; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D059010:Single-Cell Analysis; D013997:Time Factors