Distribution of driver mutations. (A-B) Distribution of IRX1 (A) and ZBTB7A alterations (B). Frameshift and nonsense mutations are shown in red and orange, respectively, and missense mutations are shown in blue. (C) The 33 regions of the partial tandem duplication of RUNX1 (RUNX1-PTD) found in 28 ML-DS samples (top) and a schematic representation of the RUNX1-PTD structure (bottom). The most common SVs result from the duplication of a genomic region encompassing RUNX1 exons 3 to 6 (RUNX1C-PTD [Ex3-6]). The variant was annotated as RUNX1C (NM_001754.4). Filled squares indicate coding exons and orange squares indicate runt-homology domains (RHD). P1: distal promoter; P2: proximal promoter; A: RUNX1A isoform-specific last exon. (D) Schematic presentation of RUNX1 isoforms produced from RUNX1-PTD. Only RUNX1C-PTD is expressed from the P1 promoter, whereas RUNX1A and RUNX1B and their PTD isoforms are expressed from the duplicated P2 promoters. (E) Paired associations among somatic mutations and cytogenetic abnormalities observed in at least 3% of patients with ML-DS. Significantly co-occurring and mutually exclusive mutations are indicated by red and blue circles, respectively. Odds ratios and associated q-values are indicated by the color gradient and size of the circles, respectively. Proteindel, protein in-frame deletion; Proteinins, protein in-frame insertion. Lollipop plots were generated using ProteinPaint (https://pecan.stjude.cloud/proteinpaint).