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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 karyo...

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Main Authors: Leppä, Aino-Maija (Author) , Grimes, Karen (Author) , Jeong, Hyobin (Author) , Huang, Frank Y. (Author) , Andrades, Alvaro (Author) , Waclawiczek, Alexander (Author) , Boch, Tobias (Author) , Jauch, Anna (Author) , Renders, Simon (Author) , Stelmach, Patrick (Author) , Müller-Tidow, Carsten (Author) , Karpova, Darja (Author) , Sohn, Markus (Author) , Grünschläger, Florian (Author) , Hasenfeld, Patrick (Author) , Benito Garagorri, Eva (Author) , Thiel, Vera (Author) , Dolnik, Anna (Author) , Rodriguez-Martin, Bernardo (Author) , Bullinger, Lars (Author) , Mrózek, Krzysztof (Author) , Eisfeld, Ann-Kathrin (Author) , Krämer, Alwin (Author) , Sanders, Ashley D. (Author) , Korbel, Jan Oliver (Author) , Trumpp, Andreas (Author)
Format: Article (Journal)
Language:English
Published: 25 November 2024
In: Nature genetics
Year: 2024, Volume: 56, Issue: 12, Pages: 2790-2803, [1-15]
ISSN:1546-1718
DOI:10.1038/s41588-024-01999-x
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41588-024-01999-x
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41588-024-01999-x
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Author Notes:Aino-Maija Leppä, Karen Grimes, Hyobin Jeong, Frank Y. Huang, Alvaro Andrades, Alexander Waclawiczek, Tobias Boch, Anna Jauch, Simon Renders, Patrick Stelmach, Carsten Müller-Tidow, Darja Karpova, Markus Sohn, Florian Grünschläger, Patrick Hasenfeld, Eva Benito Garagorri, Vera Thiel, Anna Dolnik, Bernardo Rodriguez-Martin, Lars Bullinger, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Alwin Krämer, Ashley D. Sanders, Jan O. Korbel, Andreas Trumpp
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Summary: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.
Item Description:Gesehen am 21.01.2025
Physical Description:Online Resource
ISSN:1546-1718
DOI:10.1038/s41588-024-01999-x

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