Fig. 2: The mutational landscape and gene expression signature of CIMP leukemias suggest similarity with ETP-ALL and a very early lymphoid progenitor as the cell of origin.

a Oncoprint displaying single nucleotide variants (SNVs), small inserts and deletions (indels) or copy number alterations (CNAs) affecting genes mutated in at least 2% of the cohort (n = 14). Columns correspond to patients and rows correspond to genes, ranked by mutational frequency. Variant calling was performed with an ensemble of tools on whole exome sequencing (WES) data. Different variants are indicated in different colors as shown in the plot legend. CNG = copy number gains; CNL = copy number losses. b Heatmap displaying large CNAs in CIMP cases, detected using CNVkit on WES data (n = 14). Red indicates a CNG and blue indicates a CNL. c Expression of myeloid markers commonly used for leukemia classification in CIMP (n = 13), AML (n = 211), T-ALL (n = 100) and healthy controls (n = 9). Markers used to define T/M MPAL or ETP-ALL are indicated. The lower and upper edges of the boxplots represent the first and third quartiles, respectively, the horizontal line inside the box indicates the median. The whiskers extend to the most extreme values within the range comprised between the median and 1.5 times the interquartile range. The circles represent outliers outside this range. The horizontal black lines between boxes represent pairwise comparisons between CIMP and other leukemias. Statistical significance was determined by a two-sided Wald test in the DESeq2 package and corrected for multiple testing with the Benjamini–Hochberg procedure. d Same as c, but showing lymphoid markers instead. e Bar plot showing the top results from gene set enrichment analysis (GSEA) conducted on a custom version of the MSigDB C2 collection. The analysis was conducted on differentially expressed genes in CIMP relative to AML (top), T-ALL (middle) and CD34+ HSPCs (bottom). f Heatmap displaying CIBERSORTx scores for various hematopoietic cell types, using a signature matrix derived from publicly available single-cell RNA-seq¹⁴³. The 25%-trimmed mean of the scores was calculated for each leukemia subgroup (or CD34+ cells), followed by row-wise Z-score normalization. Scores were calculated for every sample and aggregated by disease groups: CIMP (n = 13), AML (n = 189), CEBPA double mutant (DM) AML (n = 22), T-ALL (n = 100). The CEBPA DM subgroup was analyzed separately owing to the similarities with CIMP leukemias. CLP common lymphoid progenitor, CMP common myeloid progenitor, GMP granulocyte-monocyte progenitor, HSC hematopoietic stem cell, MEP megakaryocyte-erythrocyte progenitor, MLP multi-lymphoid progenitor, MPP multipotent progenitor.