Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia
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Date
2024
Publication Type
Journal Article
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yes
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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.
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Publication status
published
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Journal / series
Volume
15 (1)
Pages / Article No.
9402
Publisher
Nature
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Edition / version
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Date collected
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Subject
Acute myeloid leukaemia; Data integration; Predictive markers; Single-cell imaging
Organisational unit
02892 - NEXUS Personalized Health / NEXUS Personalized Health
09595 - Snijder, Berend (ehemalig) / Snijder, Berend (former)
02072 - Proteomics Plattform D-HEST
09735 - Bodenmiller, Bernd / Bodenmiller, Bernd
03790 - Beerenwinkel, Niko / Beerenwinkel, Niko
09568 - Rätsch, Gunnar / Rätsch, Gunnar
02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology