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, Olivér Vilinovszki, Mattheus H. E. Wildschut, Tharshika Thavayogarajah, Disha Malani, Rudolf Aebersold, Melike Ak, Faisal Alquaddoomi, Silvana I. Albert, Jonas Albinus, Ilaria Alborelli, Sonali Andani, Per-Olof Attinger, Marina Bacac, Daniel Baumhoer, Beatrice Beck‐Schimmer, Niko Beerenwinkel, Christian Beisel, Lara Bernasconi, Anne Bertolini, Bernd Bodenmiller, Ximena Bonilla, Lars Bosshard, Byron Calgua, Natalia Chicherova, Maya D’Costa, Esther Danenberg, Natalie R. Davidson, Monica-Andreea Drăgan, Reinhard Dummer, Stefanie Engler, Martin Erkens, Katja Eschbach, Cinzia Esposito, André Fedier, Pedro Ferreira, Joanna Ficek-Pascual, Anja Frei, Bruno S. Frey, Sandra Goetze, Linda Grob, Gabriele Gut, Detlef Günther, Pirmin Haeuptle, Viola Heinzelmann‐Schwarz, Sylvia Herter, René Holtackers, Tamara Huesser, Alexander Immer, Anja Irmisch, Tim M. Jaeger, Katharina Jahn, Alva Rani James, Philip Jermann, André Kahles, Abdullah Kahraman, Viktor H. Koelzer, Werner Kuebler, Jack Kuipers, Christian P. Kunze, Christian Kurzeder, Kjong-Van Lehmann, Mitchell P. Levesque, Flavio C. Lombardo, Sebastian Lugert, Gerd Maass, Philipp Markolin, Martin Mehnert, Julien Mena, Julian M. Metzler, Nicola Miglino, Holger Moch, Simone Muenst, Riccardo Murri, Charlotte K.Y. Ng, Stefan Nicolet, Marta Nowak, Mónica Núñez López, Patrick G. A. Pedrioli, Lucas Pelkmans, Salvatore Piscuoglio
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. The molecular mechanisms underlying drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML) remain to be explored. Here, the use of bulk and single cell multi-omics and ex vivo drug profiling for 21 rrAML patients reveals mechanisms of resistance to the Bcl-2 inhibitor venetoclax and treatment vulnerabilities.