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. 2024 Oct 30;15:9402. doi: 10.1038/s41467-024-53535-4

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

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Fig. 3 — a Definition of innate and treatment-related VEN resistance. Shown are VEN PCY scores for samples exposed to VEN at the time of sampling (treatment-related resistance, n = 7 samples from 5 patients) and VEN naive samples (n = 21 samples from 12 patients). Within the VEN naive samples, the spread of response scores defines the amount of innate resistance, with lower response scores indicating higher resistance. b RNA and protein levels of the VEN target Bcl-2 measured by scRNA-seq and CyTOF, averaged across all AML blasts per sample. Scatterplots show Bcl-2 levels as a function of innate resistance in VEN naive samples. Linear regression lines with 95% confidence bands, Pearson’s R, and corresponding P values (two-sided t-test) are indicated. Box plots compare Bcl-2 levels between VEN naive and exposed samples, P values from two-tailed Welch’s t-test. c t-SNE of scRNA-seq data, showing only cells classified as AML (n = 40’369 cells, 24 samples, 18 patients). Left: colored by prior VEN exposure, middle: colored by PCY-based VEN ex vivo response, right: colored by BCL2 expression. d Association of known genes involved in VEN resistance with innate or treatment-related VEN resistance. Values are derived from bulkified scRNA-seq AML cell transcriptomes. For treatment-related resistance, effect size corresponds to the delta mean gene expression between samples from patients that were or were not exposed to venetoclax, and P value was calculated using a two-sided Welch’s t-test. For innate resistance, the effect size and P value are obtained from a linear regression modeling gene expression as a function of VEN PCY score (see (a, b)). e Protein (left) and RNA (right) levels of CD36 as a function of VEN PCY score. Linear regression lines with 95% confidence bands, Pearson’s R, and corresponding P values (two-sided t-test) are indicated. f t-SNE as in (c), colored by expression of CD36. All analyses presented here were performed on samples with >5% blast content. In (a, b, and d), samples from patients who received venetoclax in earlier previous treatment lines were excluded. Number of samples (n.sam) and number of patients (n.pat) are annotated. Box plots indicate the median (horizontal line) and 25% and 75% ranges (box) and whiskers indicate the 1.5x interquartile range above or below the box.