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 Castillo, Franziska Singer, Sujana Sivapatham, Nora C. Toussaint, Oliver Vilinovszki, Mattheus H. E. Wildschut, Tharshika Thavayogarajah, Disha Malani, 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 () and Alexandre P. A. Theocharides ()
Additional contact information
Rebekka Wegmann: ETH Zurich
Ximena Bonilla: ETH Zurich
Ruben Casanova: University of Zurich
Stéphane Chevrier: University of Zurich
Ricardo Coelho: University Hospital Basel and University of Basel
Cinzia Esposito: University of Zurich
Joanna Ficek-Pascual: ETH Zurich
Sandra Goetze: ETH Zurich
Gabriele Gut: University of Zurich
Francis Jacob: University Hospital Basel and University of Basel
Andrea Jacobs: University of Zurich
Jack Kuipers: ETH Zurich
Ulrike Lischetti: University Hospital Basel and University of Basel
Julien Mena: ETH Zurich
Emanuela S. Milani: ETH Zurich
Michael Prummer: SIB Swiss Institute of Bioinformatics
Jacobo Sarabia Castillo: University of Zurich
Franziska Singer: SIB Swiss Institute of Bioinformatics
Sujana Sivapatham: University of Zurich
Nora C. Toussaint: SIB Swiss Institute of Bioinformatics
Oliver Vilinovszki: University Hospital Zurich
Mattheus H. E. Wildschut: ETH Zurich
Tharshika Thavayogarajah: University Hospital Zurich
Disha Malani: Harvard Medical School and Dana-Farber Cancer Institute
Rudolf Aebersold: ETH Zurich
Marina Bacac: Roche Innovation Center Zurich
Niko Beerenwinkel: SIB Swiss Institute of Bioinformatics
Christian Beisel: ETH Zurich
Bernd Bodenmiller: University of Zurich
Viola Heinzelmann-Schwarz: University Hospital Basel and University of Basel
Viktor H. Koelzer: University Hospital Zurich
Mitchell P. Levesque: University Hospital Zurich
Holger Moch: University Hospital Zurich
Lucas Pelkmans: University of Zurich
Gunnar Rätsch: ETH Zurich
Markus Tolnay: University Hospital Basel
Andreas Wicki: University Hospital Zurich
Bernd Wollscheid: ETH Zurich
Markus G. Manz: University Hospital Zurich
Berend Snijder: ETH Zurich
Alexandre P. A. Theocharides: University Hospital Zurich

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-53535-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53535-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-53535-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().