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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.

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Soumis le : vendredi 19 juin 2020 - 02:51:02
Dernière modification le : jeudi 4 août 2022 - 17:27:58

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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, American Society of Hematology, 2018, 132 (2), pp.187-196. ⟨10.1182/blood-2018-03-837781⟩. ⟨hal-02874598⟩



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