Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia

Autor: 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
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Nature Communications, Vol 15, Iss 1, Pp 1-18 (2024)
Druh dokumentu: article
ISSN: 2041-1723
DOI: 10.1038/s41467-024-53535-4
Popis: 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.
Databáze: Directory of Open Access Journals
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