Acute erythroid leukemia (AEL) is characterized by distinct morphology, mutational spectrum, a lack of preclinical models and poor prognosis. We have recently defined the genetic and transcriptome landscapes of this disease (Iacobucci I. et al. Nature Genetics 2019) and here we used multiplexed genome editing of mouse hematopoietic stem and progenitor cells to induce combination of loss of function mutations in recurrently mutated genes and develop preclinical models of AEL.  We demonstrated the central role of mutational cooperativity in determining leukemia lineage. Combination of mutations in Bcor, Trp53, Dnmt3a, Rb1 and Nfix specified erythroid phenotype, and were accompanied by the acquisition of alterations in signaling genes and transcription factors that recapitulated the genomic features of human AEL. Bulk transcriptome sequencing and methylation array analysis showed that mouse and human AEL exhibited deregulation of genes regulating erythroid development, notably Gata1, Klf1, and Nfe2, driven by the interaction of mutations of the epigenetic modifiers Dnmt3a and Tet2 that perturbed methylation and thus expression of lineage-specific transcription factors. We showed that fluctuation in mutational clonal composition drives changes in leukemia phenotype. In a triple Bcor/Rb1/Trp53-mutant AEL model, we observed expansion of cells with mixed AEL/B lymphoid phenotype (GATA1+, CD44+, B220+, CD19+, PAX5+) in secondary passages. To investigate phenotypic architecture, we performed full-length RNA-sequencing (SMART-seq, Takara) coupled with high parameter flow cytometric immunophenotyping that identified four gene expression clusters associated to distinct leukemia phenotype. Immature hematopoietic cells with expression of both primitive erythroid and lymphoid markers and progenitor erythroid cells were predominant in the primary tumor, while more differentiated erythroid cells and mixed B-lymphoid/erythroid cells were dominant in the secondary tumor passage. Single-cell RNA seq identified an alternative isoform of Bcor in mixed B/erythroid cells due to a larger Bcor gene deletion. In contrast to the truncated Bcor alleles induced by genome editing in the primary tumor, expression of this BCOR isoform was associated with downregulation of components of non-canonical polycomb repressive complex 1 (PRC1.1) and overexpression of its repressed target genes, including lymphoid markers. Overall, integrated single-cell genomic/transcriptomic profiling directly demonstrated the relationship of initiating and secondary genomic lesions and their relationship to leukemic phenotype.