Figure 3.
Liver-derived ANKL cells acquire a more aggressive phenotype characterized by an enriched Myc pathway. (A) Schema for generating organ–derived ANKL cells. To select liver-derived cells, ANKL cells were collected from the PDX liver and transplanted into a mouse. After 3 to 4 weeks, cells were again collected from the liver of this mouse and transplanted into another mouse. We repeated the procedure 10 times in total. Spleen-derived ANKL cells were selected in the same way from PDX spleens. (B) Survival curve of PDX mice transplanted with 1 × 103 liver- or spleen-derived ANKL1 cells (n = 8 in each group). (C) Merged uniform manifold approximation and projection (UMAP) of liver-derived ANKL1 cells (17 039 cells) and spleen-derived ANKL cells (14 034 cells) (left). Liver-derived cells were isolated from the liver of PDX transplanted with liver-derived ANKL1 cells and spleen-derived cells were isolated from the spleen of PDX transplanted with spleen-derived ANKL1 cells (n = 1 for each cell type). Liver-derived ANKL1 cells are highlighted in red (right lower). Clusters 0, 2, 5, 8, and 11 are mainly composed of liver-derived cells; clusters 1, 3, 4, 6, 9, and 14 are spleen-derived cells; clusters 7, 10, 12, and 13 are mixed with liver- and spleen-derived cells. (D) Expression levels of typical cell cycle marker genes, MKI67 and TOP2A, were overlaid on a UMAP representation (left) and their violin plots are shown on the right. (E) The top 10 enriched gene sets listed by GSEA using hallmark gene sets of the Molecular Signature Database in liver-derived ANKL1 cells compared with those in spleen-derived ANKL1 cells (left). Enrichment plot of hallmark Myc targets v1 (right). (F) Comparison of significantly differentiated leading-edge genes in the hallmark Myc target v1 between liver- and spleen-derived ANKL1 cells. (G) Gene expression levels of MYC in normal NK cells, spleen-derived ANKL cells, and liver-derived ANKL cells. (H) The expression level of MYC was overlaid on a UMAP representation (left) and its violin plot is shown on the right. (I) Immunohistochemistry (IHC) of Myc in the liver section of a patient with newly diagnosed ANKL revealing variable expression of Myc among ANKL cells (black arrow indicates expression of Myc). Scale bar, 50 μm. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001.

Liver-derived ANKL cells acquire a more aggressive phenotype characterized by an enriched Myc pathway. (A) Schema for generating organ–derived ANKL cells. To select liver-derived cells, ANKL cells were collected from the PDX liver and transplanted into a mouse. After 3 to 4 weeks, cells were again collected from the liver of this mouse and transplanted into another mouse. We repeated the procedure 10 times in total. Spleen-derived ANKL cells were selected in the same way from PDX spleens. (B) Survival curve of PDX mice transplanted with 1 × 103 liver- or spleen-derived ANKL1 cells (n = 8 in each group). (C) Merged uniform manifold approximation and projection (UMAP) of liver-derived ANKL1 cells (17 039 cells) and spleen-derived ANKL cells (14 034 cells) (left). Liver-derived cells were isolated from the liver of PDX transplanted with liver-derived ANKL1 cells and spleen-derived cells were isolated from the spleen of PDX transplanted with spleen-derived ANKL1 cells (n = 1 for each cell type). Liver-derived ANKL1 cells are highlighted in red (right lower). Clusters 0, 2, 5, 8, and 11 are mainly composed of liver-derived cells; clusters 1, 3, 4, 6, 9, and 14 are spleen-derived cells; clusters 7, 10, 12, and 13 are mixed with liver- and spleen-derived cells. (D) Expression levels of typical cell cycle marker genes, MKI67 and TOP2A, were overlaid on a UMAP representation (left) and their violin plots are shown on the right. (E) The top 10 enriched gene sets listed by GSEA using hallmark gene sets of the Molecular Signature Database in liver-derived ANKL1 cells compared with those in spleen-derived ANKL1 cells (left). Enrichment plot of hallmark Myc targets v1 (right). (F) Comparison of significantly differentiated leading-edge genes in the hallmark Myc target v1 between liver- and spleen-derived ANKL1 cells. (G) Gene expression levels of MYC in normal NK cells, spleen-derived ANKL cells, and liver-derived ANKL cells. (H) The expression level of MYC was overlaid on a UMAP representation (left) and its violin plot is shown on the right. (I) Immunohistochemistry (IHC) of Myc in the liver section of a patient with newly diagnosed ANKL revealing variable expression of Myc among ANKL cells (black arrow indicates expression of Myc). Scale bar, 50 μm. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001.

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