Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia

Pierre Hirsch (1, 2, 3) , Yanyan Zhang (4) , Ruoping Tang (1) , Virginie Joulin (4) , Hélène Boutroux (2, 3, 5) , Elodie Pronier (6) , Hannah Moatti (2, 3) , Pascale Flandrin (2, 3) , Christophe Marzac (1, 5) , Dominique Bories (7) , Fanny Fava (2) , Hayat Mokrani (6) , Aline Betems (6) , Florence Lorre (1) , Rémi Favier (1, 5) , Frédéric Féger (1, 5) , Mohamad Mohty (2, 3) , Luc Douay (2, 1, 5) , Ollivier Legrand (2, 3, 1) , Chrystèle Bilhou-Nabera (2, 3, 1, 5) , Fawzia Louache (4) , François Delhommeau (2, 3, 1, 5)

1 CHU Saint-Antoine [AP-HP]
2 UMRS893 - Centre de Recherche Saint-Antoine
3 MYPAC
4 U1170 Inserm - Hématopoïèse normale et pathologique
5 CHU Trousseau [APHP]
6 IGR - Institut Gustave Roussy
7 Hématologie moléculaire [CHU Mondor]

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.

Domaines: Génétique

Pierre Hirsch, Yanyan Zhang, Ruoping Tang, Virginie Joulin, Hélène Boutroux, et al.. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia. Nature Communications, 2016, 7, pp.12475. ⟨10.1038/ncomms12475⟩. ⟨hal-01358183⟩