Figure 1.
Single-cell transcriptome analysis identifies a subset of RA-resistant PLZF-RARA leukemic cells with a specific signature. (A-B) Uniform Manifold Approximation and Projection (UMAP) visualization of the scRNA-seq data set colored by (A) condition (NT and RA day 7 [d7]) and by (B) cluster (total integrated cells: 11 900). Six clusters were identified: ReP, DNA repair/Replication/Proliferation; Prom1-3, Promyelocyte (Neutrophil) 1-3; NeuRA1-2, Neutrophil RA1-2. (C) (Bottom) NT and RA cell distribution in each cluster. The black line indicates expected NT and RA cell proportions according to the data set size. (Top) Absolute cell number per cluster and per condition. Names of the clusters for which the proportion of NT or RA cells is significantly higher than expected (P < .01) are purple for NT cells and orange for RA cells. (D) Differentiation trajectory. (Top) Schematic representation of the different states (A-E) in each trajectory (trajectory 1: A-C-D, trajectory 2: A-C-E, trajectory 3: A-B). (Bottom) UMAP is colored according to the pseudotime value of each cell. (E) Cluster distribution in each state of the pseudotime. (F) NT and RA cell distribution (bottom: percentage; top: absolute) in each state of the pseudotime. (C and F) Names of the clusters for which the proportion of NT or RA cells was significantly higher than expected (P < .01) are purple for NT cells and orange for RA cells. (G) Violin plots showing PML-RARA response and (H) E2f signature scores in each cluster. (G and H) The signature score represents the global expression of annotated genes for the selected signature. Gray/black arrows pointing down/up: significant lower/higher expression in the cluster against all the others (average score difference > 0.02 and adjusted P < .05). (I) Violin plot showing Usp37 expression in each cluster. Black arrows pointing up: significant higher expression in the cluster against all the others (average log2|FC|> .1 and adjusted P < .05). (J) Gating strategy for isolating ProReP cells (Prom1-3 and ReP) and NeuRA (NeuRA1-2). The donut plot represents the proportion of Prom1-3 and ReP cells into the ProReP population according to the scRNA-seq analysis. (K) PLZF-RARA (black arrow: full length; black star: degraded form) levels in untreated (NT) and treated promyelocytes (RA d7). Actin is used as loading control. (L) Survival rate of mice transplanted with ProReP or NeuRA cells. Each cohort contains at least 5 mice. ∗∗∗P < .001.

Single-cell transcriptome analysis identifies a subset of RA-resistant PLZF-RARA leukemic cells with a specific signature. (A-B) Uniform Manifold Approximation and Projection (UMAP) visualization of the scRNA-seq data set colored by (A) condition (NT and RA day 7 [d7]) and by (B) cluster (total integrated cells: 11 900). Six clusters were identified: ReP, DNA repair/Replication/Proliferation; Prom1-3, Promyelocyte (Neutrophil) 1-3; NeuRA1-2, Neutrophil RA1-2. (C) (Bottom) NT and RA cell distribution in each cluster. The black line indicates expected NT and RA cell proportions according to the data set size. (Top) Absolute cell number per cluster and per condition. Names of the clusters for which the proportion of NT or RA cells is significantly higher than expected (P < .01) are purple for NT cells and orange for RA cells. (D) Differentiation trajectory. (Top) Schematic representation of the different states (A-E) in each trajectory (trajectory 1: A-C-D, trajectory 2: A-C-E, trajectory 3: A-B). (Bottom) UMAP is colored according to the pseudotime value of each cell. (E) Cluster distribution in each state of the pseudotime. (F) NT and RA cell distribution (bottom: percentage; top: absolute) in each state of the pseudotime. (C and F) Names of the clusters for which the proportion of NT or RA cells was significantly higher than expected (P < .01) are purple for NT cells and orange for RA cells. (G) Violin plots showing PML-RARA response and (H) E2f signature scores in each cluster. (G and H) The signature score represents the global expression of annotated genes for the selected signature. Gray/black arrows pointing down/up: significant lower/higher expression in the cluster against all the others (average score difference > 0.02 and adjusted P < .05). (I) Violin plot showing Usp37 expression in each cluster. Black arrows pointing up: significant higher expression in the cluster against all the others (average log2|FC|> .1 and adjusted P < .05). (J) Gating strategy for isolating ProReP cells (Prom1-3 and ReP) and NeuRA (NeuRA1-2). The donut plot represents the proportion of Prom1-3 and ReP cells into the ProReP population according to the scRNA-seq analysis. (K) PLZF-RARA (black arrow: full length; black star: degraded form) levels in untreated (NT) and treated promyelocytes (RA d7). Actin is used as loading control. (L) Survival rate of mice transplanted with ProReP or NeuRA cells. Each cohort contains at least 5 mice. ∗∗∗P < .001.

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