Figure 6.
Leukemic growth is driven by MAPK signaling and Myc activation. (A) Transcriptional blast identified based on Cibersort profiling using published single cell data sets, specifically focusing on short-term and long-term stem cells, and multipotent progenitors. (B) Characterization of disease similarity of p53 blasts based on Cibersort profiling, published RNA sequencing data sets of murine leukemias with focus on acute erythroid leukemia (AEL), AML, and B-cell acute lymphoblastic leukemia (B-ALL). (C) Estimating the activity of transcription factors based on abundance changes of their targets (input: full list of differentially expressed gene blasts vs control) as a proxy of their activity using method DoRothEA positive scores to determine transcription factor (TF) in blasts compared with the nonleukemic controls. (D) Pathway response signature scores for 14 pathways inferred from differentially expressed genes between Csnk1a1–/+ p53mut leukemic blasts vs nonleukemic control using the method PROGENy (pathway responsive genes for activity inference). (E) Volcano plot showing differentially expressed genes between leukemic blasts vs control. Positive Log2FC: overexpressed in blasts; negative Log2FC: downregulated in blasts. (F) Volcano plot showing differentially expressed genes between Csnk1a1–/+ p53mut leukemic blasts vs control with genes belonging to Hallmark pathway “MYC targets.” Positive Log2FC: overexpressed in blasts; negative Log2FC: downregulated in blasts. (G) Putative interactome downstream of p53 dysfunction and Csnk1a1 haploinsufficiency inferred using method CARNIVAL (CAusal Reasoning for Network identification using Integer VALue programming). (H) Western blot analysis of MAPK1/3, MAPK8, Myc, and b-actin in Csnk–/+ p53 blasts, Csnk1a1fl/+ or Mx1-Cre HoxB8-Flt3 cells. (I) Western blot analysis of Myc and B-actin on bone marrow samples of mice that underwent tertiary transplantation and were untreated or treated with A51 compound (related to Figure 5). Blast percentage found in bone marrow is depicted at the bottom of the blot. (J) MYC expression in RNA sequencing data of 114 samples from patients with del(5q) MDS (p53 mutation, n = 22; p53 WT, n = 92) and 400 samples of MDS with normal karyotype (p53 mutation, n = 8; p53 WT, n = 392). (K) MYC expression in RNA sequencing data of 38 samples from patients with AML with del(5q) (p53 mutation, n = 26; p53 WT, n = 12) and 51 samples from patients with AML with normal karyotype and wild-type p53. (L) PRDX4 expression in RNA sequencing data of 38 samples from patients with AML with del(5q) (p53 mutation, n = 26; p53 WT, n = 12) and 51 samples from patients with AML with normal karyotype and wild-type p53.

Leukemic growth is driven by MAPK signaling and Myc activation. (A) Transcriptional blast identified based on Cibersort profiling using published single cell data sets, specifically focusing on short-term and long-term stem cells, and multipotent progenitors. (B) Characterization of disease similarity of p53 blasts based on Cibersort profiling, published RNA sequencing data sets of murine leukemias with focus on acute erythroid leukemia (AEL), AML, and B-cell acute lymphoblastic leukemia (B-ALL). (C) Estimating the activity of transcription factors based on abundance changes of their targets (input: full list of differentially expressed gene blasts vs control) as a proxy of their activity using method DoRothEA positive scores to determine transcription factor (TF) in blasts compared with the nonleukemic controls. (D) Pathway response signature scores for 14 pathways inferred from differentially expressed genes between Csnk1a1–/+ p53mut leukemic blasts vs nonleukemic control using the method PROGENy (pathway responsive genes for activity inference). (E) Volcano plot showing differentially expressed genes between leukemic blasts vs control. Positive Log2FC: overexpressed in blasts; negative Log2FC: downregulated in blasts. (F) Volcano plot showing differentially expressed genes between Csnk1a1–/+ p53mut leukemic blasts vs control with genes belonging to Hallmark pathway “MYC targets.” Positive Log2FC: overexpressed in blasts; negative Log2FC: downregulated in blasts. (G) Putative interactome downstream of p53 dysfunction and Csnk1a1 haploinsufficiency inferred using method CARNIVAL (CAusal Reasoning for Network identification using Integer VALue programming). (H) Western blot analysis of MAPK1/3, MAPK8, Myc, and b-actin in Csnk–/+ p53 blasts, Csnk1a1fl/+ or Mx1-Cre HoxB8-Flt3 cells. (I) Western blot analysis of Myc and B-actin on bone marrow samples of mice that underwent tertiary transplantation and were untreated or treated with A51 compound (related to Figure 5). Blast percentage found in bone marrow is depicted at the bottom of the blot. (J) MYC expression in RNA sequencing data of 114 samples from patients with del(5q) MDS (p53 mutation, n = 22; p53 WT, n = 92) and 400 samples of MDS with normal karyotype (p53 mutation, n = 8; p53 WT, n = 392). (K) MYC expression in RNA sequencing data of 38 samples from patients with AML with del(5q) (p53 mutation, n = 26; p53 WT, n = 12) and 51 samples from patients with AML with normal karyotype and wild-type p53. (L) PRDX4 expression in RNA sequencing data of 38 samples from patients with AML with del(5q) (p53 mutation, n = 26; p53 WT, n = 12) and 51 samples from patients with AML with normal karyotype and wild-type p53.

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