%0 Journal Article
%A Hablesreiter, Raphael
%A Strzelecka, Paulina M
%A Kopp, Klara
%A Estrada, Natalia
%A Dolnik, Anna
%A Tilgner, Marlon
%A Fustero-Torre, Coral
%A Thol, Felicitas
%A Heidel, Florian H
%A Heuser, Michael
%A Haghverdi, Laleh
%A Bullinger, Lars
%A Christen, Friederike
%A Damm, Frederik
%T Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution.
%J Experimental hematology & oncology
%V 14
%N 1
%@ 2162-3619
%C London
%I Biomed Central
%M DKFZ-2025-02227
%P 127
%D 2025
%X Reconstructing and understanding intra-tumor heterogeneity, the coexistence of multiple genetically distinct subclones within the tumor of a patient, and tumor development is essential for resolving carcinogenesis and for identifying mechanisms of therapy resistance. While bulk sequencing can provide a broad view on tumoral complexity/heterogeneity of a patient, single-cell analysis remains essential to identify rare subclones that might drive chemotherapy resistance. In this study, we performed an integrated analysis of bulk and single-cell DNA sequencing data of core-binding factor acute myeloid leukemia patients, defined by the presence of a RUNX1::RUNX1T1 or CBFB::MYH11 fusion gene. By single-cell sequencing, we inferred tumor phylogenies for 8 patients at diagnosis including patient-specific somatic variants, somatic copy-number alterations and fusion genes, and studied clonal evolution under the pressure of chemotherapy for 3 patients. As a result, we developed an approach to reliably integrate subclonal somatic copy number alterations into phylogenetic trees and clonal evolution analysis, obtaining unprecedented resolution of intra-tumor heterogeneity in CBF AML. We were able to show that the fusion gene is among the earliest events of leukemogenesis at single-cell level. We identified remaining tumor clones in 6 patients with complete remission samples indicating incomplete eradication of the tumor clones. Here, we show that identifying the order of mutation acquisition can provide valuable insights into evolutionary history, offering a framework to improve drug selection in the era of targeted therapies.
%K AML (Other)
%K CBF (Other)
%K Clonal evolution (Other)
%K Clonal heterogeneity (Other)
%K Intra-tumor heterogeneity (Other)
%K Single-cell DNA sequencing (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41152985
%R 10.1186/s40164-025-00718-4
%U https://inrepo02.dkfz.de/record/305557