Figure 5.
Clonal evolution of iAMP21-ALL using scRNA-seq. (A) Uniform manifold approximation and projection (UMAP) representation of the scRNA-seq data set from patient SJBALL021901. Clusters of cells are colored based on the cell types. (B) scRNA-seq derived copy number profiles for blast cells in patient SJBALL021901. Copy number profiles from WGS are shown (top); chromosomes with copy number gains are labeled. Three clusters were observed via scRNA-seq: C1 has the lowest copy number of chromosome 21 and no copy number gain of chromosome 14. C2 has an intermediate copy number gain of chromosome 21 together with copy number gain of chromosome 14. C3 has the highest copy number of chromosome 21 with no copy number gain of chromosome 14. Chromosome 21 is shown (right). (C) UMAP representation of the scRNA-seq data for SJBALL021901 colored based on the 3 copy number clusters. Healthy cells are shown in gray. (D) Heatmap showing copy number profiles of chromosome 21 derived from WGS data of SJBALL021901. Differentially expressed genes between blasts and healthy cells based on scRNA-seq are labeled on the top in red and blue for genes with higher and lower expression in blasts, respectively. Nine segments with varying copy number patterns are labeled at the bottom. (E) Violin plot showing the expression profile of 3 selected genes across different copy number clusters and healthy cells in SJBALL021901. (F) Scatterplot showing copy numbers of chromosome 14 and the 9 segments on chromosome 21, as illustrated in panel D, for 70 cells with single-cell WGS in SJBALL021901. These cells were assigned to different clusters based on their copy number patterns. (G) DNA FISH image of 3 representative cells from different copy number clusters of SJBALL021901. Seven probes were used in total, paired in 4 sequential hybridizations with imaging after every hybridization. The first hybridization is RB1 (green) and CDKN2A (red), the second is ETV6 (green) and IGH (red), the third is PRMT2 (green) and C21orf91 (red), and the fourth is HMGN1 (green). The scales (5 μm) are shown in red. (H) Schematic representation of the clonal evolution model in sample SJBALL021901. C1 is an early clone with a centromeric and/or telomeric loss and lower copy number gain of the iAMP21 chromosome, followed by 2 evolutionary tracks: (1) gain of chromosome 14 and further amplification of the iAMP21 chromosome, resulting in the generation of the predominant clone C2 and (2) further amplification of the iAMP21 chromosome without the gain of chromosome 14 in C3.

Clonal evolution of iAMP21-ALL using scRNA-seq. (A) Uniform manifold approximation and projection (UMAP) representation of the scRNA-seq data set from patient SJBALL021901. Clusters of cells are colored based on the cell types. (B) scRNA-seq derived copy number profiles for blast cells in patient SJBALL021901. Copy number profiles from WGS are shown (top); chromosomes with copy number gains are labeled. Three clusters were observed via scRNA-seq: C1 has the lowest copy number of chromosome 21 and no copy number gain of chromosome 14. C2 has an intermediate copy number gain of chromosome 21 together with copy number gain of chromosome 14. C3 has the highest copy number of chromosome 21 with no copy number gain of chromosome 14. Chromosome 21 is shown (right). (C) UMAP representation of the scRNA-seq data for SJBALL021901 colored based on the 3 copy number clusters. Healthy cells are shown in gray. (D) Heatmap showing copy number profiles of chromosome 21 derived from WGS data of SJBALL021901. Differentially expressed genes between blasts and healthy cells based on scRNA-seq are labeled on the top in red and blue for genes with higher and lower expression in blasts, respectively. Nine segments with varying copy number patterns are labeled at the bottom. (E) Violin plot showing the expression profile of 3 selected genes across different copy number clusters and healthy cells in SJBALL021901. (F) Scatterplot showing copy numbers of chromosome 14 and the 9 segments on chromosome 21, as illustrated in panel D, for 70 cells with single-cell WGS in SJBALL021901. These cells were assigned to different clusters based on their copy number patterns. (G) DNA FISH image of 3 representative cells from different copy number clusters of SJBALL021901. Seven probes were used in total, paired in 4 sequential hybridizations with imaging after every hybridization. The first hybridization is RB1 (green) and CDKN2A (red), the second is ETV6 (green) and IGH (red), the third is PRMT2 (green) and C21orf91 (red), and the fourth is HMGN1 (green). The scales (5 μm) are shown in red. (H) Schematic representation of the clonal evolution model in sample SJBALL021901. C1 is an early clone with a centromeric and/or telomeric loss and lower copy number gain of the iAMP21 chromosome, followed by 2 evolutionary tracks: (1) gain of chromosome 14 and further amplification of the iAMP21 chromosome, resulting in the generation of the predominant clone C2 and (2) further amplification of the iAMP21 chromosome without the gain of chromosome 14 in C3.

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