Clonal interference of signaling mutations holds prognostic relevance in core binding factor acute myeloid leukemia.
Fiche publication
Date publication
avril 2018
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CORNILLET-LEFEBVRE Pascale
Tous les auteurs :
Itzykson R, Duployez N, Fasan A, Decool G, Marceau-Renaut A, Meggendorfer M, Jourdan E, Petit A, Lapillonne H, Micol JB, Cornillet-Lefebvre P, Ifrah N, Leverger G, Dombret H, Boissel N, Haferlach T, Preudhomme C
Lien Pubmed
Résumé
Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in Core Binding Factor Acute Myeloid Leukemias (CBF AML), 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 unknown. We analyzed a cohort of 445 patients with CBF AML adult and pediatric patients treated with intensive chemotherapy, and with deep sequencing of six signaling genes (, , , , and ). 152 (34%), 167 (38%) and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference). Clonal interference of signaling mutations was associated with older age (P=0.004) and inv(16) subtype (P=0.025) but not with WBC count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with either a single clone or clonal interference (P=0.14). The repertoire of , and / variants differed between both groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but conveyed inferior event-free survival (EFS, P<10-4) while presence of a single signaling clone did not (P=0.44). 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. We analyzed a cohort of 445 patients with CBF AML adult and pediatric patients treated with intensive chemotherapy (NCT00428558, NCT00149162), and with deep sequencing of six signaling genes (KIT, NRAS, KRAS, FLT3, JAK2 and CBL).
Référence
Blood. 2018 Apr 24;: