CG2 leukemia consists of immature megaerythroid stem and progenitor lineages. (A) Uniform manifold approximation and projection (UMAP) of normal BM lineages. The stem-megaerythroid compartment is circled, relevant populations are labeled, and differentiation trajectories are highlighted with arrows. (B) DEGs between cells of the megakaryocytic lineage (CD34⁺ MEPs, CD34⁺ MKPs, and platelets) and all other cell types in normal BM (supplemental Table 11). Genes relevant to the megakaryocytic differentiation are highlighted in red, and genes of the mitochondrial apoptotic pathway are highlighted in blue. (C, top) Percentage positive cells for each gene in mCG2s, pCG2s, other subtypes of AML and in specific populations of the normal BM (HSCs, MEPs, MKPs, and PLTs). The horizontal line represents the median of the group, the patient and models are color coded as in panel D, and the normal samples are color coded based on donor as in supplemental Figure 14D. (Bottom) ITGA2B (CD41) expression per cell on a UMAP representation of mCG2-1, pCG2-1, and normal BM (extended samples in supplemental Figures 15 and 16). (D) Radar plot (top) of lineage composition assessed by single-cell RNAseq in CG2 AMKL models and pediatric patients, as compared with diverse phenotypic and genetic subtypes of adult AML. The detailed proportion of each cell type is presented as stacked bar plots (bottom). Color coding of populations is as depicted in panel A. (E) Representation as in panel C of terminal differentiation gene expression (extended samples in supplemental Figures 15 and 16). (F) DEGs in the CD34⁺ MKPs from the mCG2 and pCG2s compared with those in normal CD34⁺ MKPs (supplemental Table 12). Selected markers are highlighted in red, and genes of the mitochondrial apoptotic pathway are highlighted in blue. (G) Representation as in panel C of BCL2 and BCL2L1 (BCL-X_L) expression. ERP, erythroid progenitors; HSCs, hematopoietic stem cells; PLT, platelet.