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| Item Type: | Letter |
|---|---|
| Title: | Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution |
| Creators Name: | Hablesreiter, Raphael, Strzelecka, Paulina M., Kopp, Klara, Estrada, Natalia, Dolnik, Anna, Tilgner, Marlon, Fustero-Torre, Coral, Thol, Felicitas, Heidel, Florian H., Heuser, Michael, Haghverdi, Laleh, Bullinger, Lars, Christen, Friederike and Damm, Frederik |
| Abstract: | 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. |
| Keywords: | AML, CBF, Intra-Tumor Heterogeneity, Clonal Evolution, Clonal Heterogeneity, Single-Cell DNA Sequencing |
| Source: | Experimental Hematology & Oncology |
| ISSN: | 2162-3619 |
| Publisher: | BioMed Central |
| Volume: | 14 |
| Number: | 1 |
| Page Range: | 127 |
| Date: | 28 October 2025 |
| Official Publication: | https://doi.org/10.1186/s40164-025-00718-4 |
| PubMed: | View item in PubMed |
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