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Nat. Genet., 25 November 2024 | https://doi.org/10.1038/s41588-024-01999-x
Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype
Aino-Maija Leppä 1,2,3,19, Karen Grimes 4,19, Hyobin Jeong 4,5,6,19, Frank Y. Huang 1,2,3, Alvaro Andrades 4, Alexander Waclawiczek 1,2, Tobias Boch 7, Anna Jauch 8, Simon Renders 1,2,9, Patrick Stelmach 1,2,9, Carsten Müller-Tidow 9, Darja Karpova 1,2, Markus Sohn 1,2, Florian Grünschläger 1,2,3, Patrick Hasenfeld 4, Eva Benito Garagorri 4, Vera Thiel 1,2,3, Anna Dolnik 10, Bernardo Rodriguez-Martin 4, Lars Bullinger 10, Krzysztof Mrózek 11,12, Ann-Kathrin Eisfeld 11,12, Alwin Krämer 13, Ashley D. Sanders 14,15,16,20, Jan O. Korbel 4,17,20,* & Andreas Trumpp 1,2,18,20,*
1Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
2Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
3Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
4European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
5Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea.
6Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
7University Hospital Mannheim, Heidelberg University, Mannheim, Germany.
8Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
9Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
10Charité Medical Department, Division of Hematology, Oncology and Tumor Immunology, Berlin, Germany.
11Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
12Clara D. Bloomfield Center for Leukemia Outcomes Research, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
13Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
14Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
15Berlin Institute of Health, Berlin, Germany.
16Charité-Universitätsmedizin, Berlin, Germany.
17Bridging Research Division on Mechanisms of Genomic Variation and Data Science, German Cancer Research Center, Heidelberg, Germany.
18German Cancer Consortium (DKTK), Heidelberg, Germany.
19These authors contributed equally: Aino-Maija Leppä, Karen Grimes, Hyobin Jeong.
20These authors jointly supervised this work: Ashley D. Sanders, Jan O. Korbel and Andreas Trumpp.
2Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
3Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
4European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
5Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea.
6Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
7University Hospital Mannheim, Heidelberg University, Mannheim, Germany.
8Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
9Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
10Charité Medical Department, Division of Hematology, Oncology and Tumor Immunology, Berlin, Germany.
11Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
12Clara D. Bloomfield Center for Leukemia Outcomes Research, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
13Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
14Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
15Berlin Institute of Health, Berlin, Germany.
16Charité-Universitätsmedizin, Berlin, Germany.
17Bridging Research Division on Mechanisms of Genomic Variation and Data Science, German Cancer Research Center, Heidelberg, Germany.
18German Cancer Consortium (DKTK), Heidelberg, Germany.
19These authors contributed equally: Aino-Maija Leppä, Karen Grimes, Hyobin Jeong.
20These authors jointly supervised this work: Ashley D. Sanders, Jan O. Korbel and Andreas Trumpp.
*Corresponding authors: correspondence to Jan O. Korbel or Andreas Trumpp
Abstract
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.
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- Research article
- 2024년 11월 (BRIC 등록일 2024-11-27)
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