Nature Communications (Oct 2024)
Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia
- Rebekka Wegmann,
- Ximena Bonilla,
- Ruben Casanova,
- Stéphane Chevrier,
- Ricardo Coelho,
- Cinzia Esposito,
- Joanna Ficek-Pascual,
- Sandra Goetze,
- Gabriele Gut,
- Francis Jacob,
- Andrea Jacobs,
- Jack Kuipers,
- Ulrike Lischetti,
- Julien Mena,
- Emanuela S. Milani,
- Michael Prummer,
- Jacobo Sarabia Del Castillo,
- Franziska Singer,
- Sujana Sivapatham,
- Nora C. Toussaint,
- Oliver Vilinovszki,
- Mattheus H. E. Wildschut,
- Tharshika Thavayogarajah,
- Disha Malani,
- The TumorProfiler Consortium,
- Rudolf Aebersold,
- Marina Bacac,
- Niko Beerenwinkel,
- Christian Beisel,
- Bernd Bodenmiller,
- Viola Heinzelmann-Schwarz,
- Viktor H. Koelzer,
- Mitchell P. Levesque,
- Holger Moch,
- Lucas Pelkmans,
- Gunnar Rätsch,
- Markus Tolnay,
- Andreas Wicki,
- Bernd Wollscheid,
- Markus G. Manz,
- Berend Snijder,
- Alexandre P. A. Theocharides
Affiliations
- Rebekka Wegmann
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich
- Ximena Bonilla
- Department of Computer Science, ETH Zurich
- Ruben Casanova
- Department of Quantitative Biomedicine, University of Zurich
- Stéphane Chevrier
- Department of Quantitative Biomedicine, University of Zurich
- Ricardo Coelho
- Department of Biomedicine, University Hospital Basel and University of Basel
- Cinzia Esposito
- Institute of Molecular Life Sciences, University of Zurich
- Joanna Ficek-Pascual
- Department of Computer Science, ETH Zurich
- Sandra Goetze
- Department of Health Sciences and Technology, ETH Zurich
- Gabriele Gut
- Institute of Molecular Life Sciences, University of Zurich
- Francis Jacob
- Department of Biomedicine, University Hospital Basel and University of Basel
- Andrea Jacobs
- Department of Quantitative Biomedicine, University of Zurich
- Jack Kuipers
- Department of Biosystems Science and Engineering, ETH Zurich
- Ulrike Lischetti
- Department of Biomedicine, University Hospital Basel and University of Basel
- Julien Mena
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich
- Emanuela S. Milani
- Department of Health Sciences and Technology, ETH Zurich
- Michael Prummer
- SIB Swiss Institute of Bioinformatics
- Jacobo Sarabia Del Castillo
- Institute of Molecular Life Sciences, University of Zurich
- Franziska Singer
- SIB Swiss Institute of Bioinformatics
- Sujana Sivapatham
- Department of Quantitative Biomedicine, University of Zurich
- Nora C. Toussaint
- SIB Swiss Institute of Bioinformatics
- Oliver Vilinovszki
- Department of Medical Oncology and Hematology, University Hospital Zurich
- Mattheus H. E. Wildschut
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich
- Tharshika Thavayogarajah
- Department of Medical Oncology and Hematology, University Hospital Zurich
- Disha Malani
- Harvard Medical School and Dana-Farber Cancer Institute
- The TumorProfiler Consortium
- Rudolf Aebersold
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich
- Marina Bacac
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich
- Niko Beerenwinkel
- SIB Swiss Institute of Bioinformatics
- Christian Beisel
- Department of Biosystems Science and Engineering, ETH Zurich
- Bernd Bodenmiller
- Department of Quantitative Biomedicine, University of Zurich
- Viola Heinzelmann-Schwarz
- Department of Biomedicine, University Hospital Basel and University of Basel
- Viktor H. Koelzer
- Department of Pathology and Molecular Pathology, University Hospital Zurich
- Mitchell P. Levesque
- Department of Dermatology, University Hospital Zurich
- Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital Zurich
- Lucas Pelkmans
- Institute of Molecular Life Sciences, University of Zurich
- Gunnar Rätsch
- Department of Computer Science, ETH Zurich
- Markus Tolnay
- Institute of Medical Genetics and Pathology, University Hospital Basel
- Andreas Wicki
- Department of Medical Oncology and Hematology, University Hospital Zurich
- Bernd Wollscheid
- Department of Health Sciences and Technology, ETH Zurich
- Markus G. Manz
- Department of Medical Oncology and Hematology, University Hospital Zurich
- Berend Snijder
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich
- Alexandre P. A. Theocharides
- Department of Medical Oncology and Hematology, University Hospital Zurich
- DOI
- https://doi.org/10.1038/s41467-024-53535-4
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 18
Abstract
Abstract Deep single-cell multi-omic profiling offers a promising approach to understand and overcome drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML). Here, we combine single-cell ex vivo drug profiling (pharmacoscopy) with single-cell and bulk DNA, RNA, and protein analyses, alongside clinical data from 21 rrAML patients. Unsupervised data integration reveals reduced ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) in patients treated with both a hypomethylating agent (HMA) and VEN, compared to those pre-exposed to chemotherapy or HMA alone. Integrative analysis identifies both known and unreported mechanisms of innate and treatment-related VEN resistance and suggests alternative treatments, like targeting increased proliferation with the PLK inhibitor volasertib. Additionally, high CD36 expression in VEN-resistant blasts associates with sensitivity to CD36-targeted antibody treatment ex vivo. This study demonstrates how single-cell multi-omic profiling can uncover drug resistance mechanisms and treatment vulnerabilities, providing a valuable resource for future AML research.
