Accéder directement au contenu Accéder directement à la navigation
Article dans une revue

Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia

Raphaël Itzykson 1 Nicolas Duployez 2, 3 Annette Fasan Gauthier Decool Alice Marceau-Renaut Manja Meggendorfer Eric Jourdan 4 Arnaud Petit 5 Hélène Lapillonne 6, 7, 8, 9 Jean-Baptiste Micol 1, 10, 11 Pascale Cornillet-Lefebvre 12 Norbert Ifrah 13 Guy Leverger 14 Hervé Dombret 15, 16, 17 Nicolas Boissel 18 Torsten Haferlach 19 Claude Preudhomme 20
Abstract :

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (, , , , , ). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age ( = .004) and inv(16) subtype ( = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference ( = .14). The repertoire of , , and / variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival ( < 10), whereas the presence of a single signaling clone did not ( = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.

Type de document :
Article dans une revue
Liste complète des métadonnées

https://hal.univ-angers.fr/hal-02874598
Contributeur : Okina Université d'Angers <>
Soumis le : vendredi 19 juin 2020 - 02:51:02
Dernière modification le : mardi 20 octobre 2020 - 03:14:07

Lien texte intégral

Identifiants

Citation

Raphaël Itzykson, Nicolas Duployez, Annette Fasan, Gauthier Decool, Alice Marceau-Renaut, et al.. Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia. Blood, 2018, 132 (2), pp.187-196. ⟨10.1182/blood-2018-03-837781⟩. ⟨hal-02874598⟩

Partager

Métriques

Consultations de la notice

36