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. 2024 Oct 30;636(8041):241–250. doi: 10.1038/s41586-024-08137-x

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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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Extended Data Fig. 10 — a, Expression of the indicated pro- and anti- apoptotic genes in FACS-sorted SA + R CMPs and GMPs measured by bulk RNA-Seq. Mean and SD from n = 3 independent experiments are shown. ns: not significant (two-tailed unpaired t-test). b, UMAP representation of integrated single-cell transcriptome data from FACS-sorted SA + R CMPs (left) and GMPs (right) from Fig. 5a,b. c, Expression of the indicated pro- and anti- apoptotic genes in the different clusters. d, Flow cytometry analysis of SA + R CB cells from the experiment shown in Fig. 5a on day 6, showing that the vast majority of ΔLNGFR-NRAS^G12D⁺ cells also express the other two transgenes (GFP-ASXL1^del1900-1922 and mCherry-SRSF2^P95L). e, Volcano plot showing differentially expressed genes between NRAS^G12D+ and WT cells of the GMP cluster from Fig. 5b,d. Significantly upregulated and downregulated genes (Wilcoxon test) are shown in red and blue, respectively. Granulocytic (MPO, AZU1, ELANE) and monocytic (S100A8, S100A9, S100A12, CD52, CCL2) lineage genes, downregulated and upregulated, respectively, are highlighted. Downregulated genes encoding ribosomal proteins are shown in green. f, Top 20 most enriched HALLMARK pathways in NRAS^G12D+ vs WT cells belonging to the GMP cluster from Fig. 5b,d. NES: normalized enrichment score. g, Viability of CD34+ LSCs from the indicated patient-derived AML-iPS cell lines with or without ectopic lentiviral expression of NRAS^G12D, treated with VEN at the indicated concentrations. %Viability compared to DMSO-treated group is shown. n = 3 for AML-4.24 treated with 12 μM VEN and n = 4 for all other groups. Mean and SD are shown. P values were calculated with a two-tailed unpaired t test. h, Summary schematic of the effects of RAS mutation acquisition in different HSPC types. RAS mutations acquired by more primitive HSPCs (HSC/MPPs or CMPs) result in reduction of GMP formation and reciprocal increase in megakaryocyte and erythroid progenitors (MEP) (left panel). Acquisition of RAS mutations in GMPs drives their differentiation towards the monocytic and away from the granulocytic lineage (right panel).