Year: 2024
Type: article
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.
DOI: 10.5167/uzh-264385
Authors: Wegmann, Rebekka, Bonilla, Ximena, Casanova, Ruben, Chevrier, Stéphane, Coelho, Ricardo, Esposito, Cinzia, Ficek-Pascual, Joanna, Goetze, Sandra, Gut, Gabriele, Jacob, Francis, Jacobs, Andrea, Kuipers, Jack, Lischetti, Ulrike, Mena, Julien, Milani, Emanuela S, Prummer, Michael, Del Castillo, Jacobo Sarabia, Singer, Franziska, Sivapatham, Sujana, Toussaint, Nora C, Vilinovszki, Oliver, Wildschut, Mattheus H E, Thavayogarajah, Tharshika, Malani, Disha, TumorProfiler Consortium, et al, Aebersold, Rudolf, Bacac, Marina, Beerenwinkel, Niko, Beisel, Christian, Bodenmiller, Bernd, Koelzer, Viktor H, Moch, Holger
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6948380164
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