TY  - JOUR
AU  - Hablesreiter, Raphael
AU  - Strzelecka, Paulina M
AU  - Kopp, Klara
AU  - Estrada, Natalia
AU  - Dolnik, Anna
AU  - Tilgner, Marlon
AU  - Fustero-Torre, Coral
AU  - Thol, Felicitas
AU  - Heidel, Florian H
AU  - Heuser, Michael
AU  - Haghverdi, Laleh
AU  - Bullinger, Lars
AU  - Christen, Friederike
AU  - Damm, Frederik
TI  - Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution.
JO  - Experimental hematology & oncology
VL  - 14
IS  - 1
SN  - 2162-3619
CY  - London
PB  - Biomed Central
M1  - DKFZ-2025-02227
SP  - 127
PY  - 2025
AB  - 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.
KW  - AML (Other)
KW  - CBF (Other)
KW  - Clonal evolution (Other)
KW  - Clonal heterogeneity (Other)
KW  - Intra-tumor heterogeneity (Other)
KW  - Single-cell DNA sequencing (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41152985
DO  - DOI:10.1186/s40164-025-00718-4
UR  - https://inrepo02.dkfz.de/record/305557
ER  -