Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype
Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage-fusion-bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug-response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.
Authors
- Alwin Krämer
- Hyobin Jeong (ORCID: https://orcid.org/0000-0002-1526-3343)
- Markus Sohn
- Anna Jauch (ORCID: https://orcid.org/0000-0002-0771-3084)
- Carsten Müller‐Tidow (ORCID: https://orcid.org/0000-0002-7166-5232)
- Aino‐Maija Leppä (ORCID: https://orcid.org/0000-0003-0849-1759)
- Florian Grünschläger (ORCID: https://orcid.org/0000-0003-0021-6912)
- Simon Renders (ORCID: https://orcid.org/0000-0001-7883-2956)
- Lars Bullinger (ORCID: https://orcid.org/0000-0002-5890-5510)
- Vera Thiel (ORCID: https://orcid.org/0000-0003-1245-0175)
- Patrick Hasenfeld (ORCID: https://orcid.org/0000-0003-2319-2482)
- Ashley D. Sanders (ORCID: https://orcid.org/0000-0003-3945-0677)
- Anna Dolnik (ORCID: https://orcid.org/0000-0003-4166-2900)
- Bernardo Rodríguez–Martín (ORCID: https://orcid.org/0000-0003-4693-3140)
- Alexander Waclawiczek (ORCID: https://orcid.org/0000-0002-8749-6736)
- Eva Benito Garagorri
- Darja Karpova (ORCID: https://orcid.org/0000-0003-0695-1854)
- Frank Y. Huang (ORCID: https://orcid.org/0000-0002-2163-9300)
- Jan O. Korbel (ORCID: https://orcid.org/0000-0002-2798-3794)
- Tobias Boch (ORCID: https://orcid.org/0000-0001-8588-4180)
- Karen Grimes (ORCID: https://orcid.org/0000-0002-4805-2366)
- Krzysztof Mrózek (ORCID: https://orcid.org/0000-0002-1408-5063)
- Andreas Trumpp (ORCID: https://orcid.org/0000-0002-6212-3466)
- Patrick Stelmach (ORCID: https://orcid.org/0009-0000-5270-4761)
- Ann‐Kathrin Eisfeld (ORCID: https://orcid.org/0000-0001-6442-1419)
- Alvaro Andrades
Institutions
- German Cancer Research Center (DE)
- Yonsei University (KR)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- European Molecular Biology Laboratory (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- DKFZ-ZMBH Alliance (DE)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- University Medical Centre Mannheim (DE)
- Hanyang University (KR)
- The Ohio State University (US)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1038/s41588-024-01999-x
- Citations
- 24
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 5.61