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

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2024年10月30日

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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,
Rudolf Aebersold,
Melike Ak,
Faisal S. Al-Quaddoomi,
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 F. Ferreira,
Joanna Ficek-Pascual,
Anja L. Frei,
Bruno Frey,
Sandra Goetze,
Linda Grob,
Gabriele Gut,
Detlef Günther,
Pirmin Haeuptle,
Viola Heinzelmann-Schwarz,
Sylvia Herter,
Rene Holtackers,
Tamara Huesser,
Alexander Immer,
Anja Irmisch,
Tim M. Jaeger,
Katharina Jahn,
Alva R. James,
Philip M. Jermann,
André Kahles,
Abdullah Kahraman,
Viktor H. Koelzer,
Werner Kuebler,
Jack Kuipers,
Christian P. Kunze,
Christian Kurzeder,
Kjong-Van Lehmann,
Mitchell 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,
Monica Nunez Lopez,
Patrick G. A. Pedrioli,
Lucas Pelkmans,
Salvatore Piscuoglio,
Michael Prummer,
Laurie Prélot,
Natalie Rimmer,
Mathilde Ritter,
Christian Rommel,
María L. Rosano-González,
Gunnar Rätsch,
Natascha Santacroce,
Jacobo Sarabia del Castillo,
Ramona Schlenker,
Petra C. Schwalie,
Severin Schwan,
Tobias Schär,
Gabriela Senti,
Wenguang Shao,
Franziska Singer,
Berend Snijder,
Bettina Sobottka,
Vipin T. Sreedharan,
Stefan Stark,
Daniel J. Stekhoven,
Tanmay Tanna,
Tinu M. Thomas,
Markus Tolnay,
Vinko Tosevski,
Nora C. Toussaint,
Mustafa A. Tuncel,
Marina Tusup,
Audrey Van Drogen,
Marcus Vetter,
Tatjana Vlajnic,
Sandra Weber,
Walter P. Weber,
Rebekka Wegmann,
Michael Weller,
Fabian Wendt,
Norbert Wey,
Mattheus H. E. Wildschut,
Shuqing Yu,
Johanna Ziegler,
Marc Zimmermann,
Martin Zoche,
Gregor Zuend,
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

摘要

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.