Figure 4.
Identification of key regulators related to cell cycle dysregulation in drug-resistant clones. (A) Inference of clonal structure from somatic mtDNA mutations for pAML1 at diagnosis (left) and relapse (right). Each column represents a cell, and rows display detected mtDNA mutations. Color indicates heteroplasmy (% allele frequency). (B) Fish plot depicts the trajectory of clonal evolution inferred from mean heteroplasmy of mtDNA mutations from diagnosis to relapse for pAML1. (C) Diagram showing the discrimination of drug-resistant and drug-sensitive clones. (D) Top 10 enriched GO terms of differentially accessible regions in drug-resistant clones as compared with drug-sensitive clones. Color indicates the significance of enrichment. (E) Gene score of T-cell regulatory genes (n = 100) compared between drug-sensitive and drug-resistant clones. ∗P < .05, paired t test. (F) Heat map presenting the changes of gene score for MHC class II genes and their regulators in drug-resistant clones as compared with drug-sensitive clones. ∗P < .05, Wilcoxon rank-sum test. (G) Gene set enrichment analysis of cell cycle signaling in drug-resistant clones as compared with drug-sensitive clones. (H) Enriched motifs in drug-resistant clones compared with drug-sensitive clones. The commonly enriched regulatory factors are highlighted. Color represents enrichment significance, with the top 5 motifs selected for each patient. (I) Interaction network of key regulators in drug-resistant clones. Each node represents a regulator, and edges indicate interaction. The node size corresponds to the frequency of interaction, whereas the line thickness indicates the strength of the interaction. (J) Footprints of resistant clone-specific enriched motifs including SP1, DNMT1, and EGR1. Lines are color-coded for drug-resistant and drug-sensitive clones. (K) Heat map displaying the relative gene score of DNMT1-p15 pathway (top) and EGR1-ID1 pathway (bottom) in drug-resistant clones as compared with drug-sensitive clones. ∗P < .05, Wilcoxon rank-sum test. GTPase, guanosine triphosphate; ncRNA, non-coding RNA; NES, normalized enrichment score.

Identification of key regulators related to cell cycle dysregulation in drug-resistant clones. (A) Inference of clonal structure from somatic mtDNA mutations for pAML1 at diagnosis (left) and relapse (right). Each column represents a cell, and rows display detected mtDNA mutations. Color indicates heteroplasmy (% allele frequency). (B) Fish plot depicts the trajectory of clonal evolution inferred from mean heteroplasmy of mtDNA mutations from diagnosis to relapse for pAML1. (C) Diagram showing the discrimination of drug-resistant and drug-sensitive clones. (D) Top 10 enriched GO terms of differentially accessible regions in drug-resistant clones as compared with drug-sensitive clones. Color indicates the significance of enrichment. (E) Gene score of T-cell regulatory genes (n = 100) compared between drug-sensitive and drug-resistant clones. ∗P < .05, paired t test. (F) Heat map presenting the changes of gene score for MHC class II genes and their regulators in drug-resistant clones as compared with drug-sensitive clones. ∗P < .05, Wilcoxon rank-sum test. (G) Gene set enrichment analysis of cell cycle signaling in drug-resistant clones as compared with drug-sensitive clones. (H) Enriched motifs in drug-resistant clones compared with drug-sensitive clones. The commonly enriched regulatory factors are highlighted. Color represents enrichment significance, with the top 5 motifs selected for each patient. (I) Interaction network of key regulators in drug-resistant clones. Each node represents a regulator, and edges indicate interaction. The node size corresponds to the frequency of interaction, whereas the line thickness indicates the strength of the interaction. (J) Footprints of resistant clone-specific enriched motifs including SP1, DNMT1, and EGR1. Lines are color-coded for drug-resistant and drug-sensitive clones. (K) Heat map displaying the relative gene score of DNMT1-p15 pathway (top) and EGR1-ID1 pathway (bottom) in drug-resistant clones as compared with drug-sensitive clones. ∗P < .05, Wilcoxon rank-sum test. GTPase, guanosine triphosphate; ncRNA, non-coding RNA; NES, normalized enrichment score.

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