Recent data suggest that NPM1-mutated AMLs are heterogeneous in terms of co-mutations and expression of transcriptomic programs and surface proteins. Such heterogeneity may reflect a variable differentiation blockade of leukemic cells. Indeed, blasts in some NPM1-mutated AMLs may display an immature progenitor morphology, immunophenotype, and transcriptional program, or have a more mature monocytic and/or dendritic differentiation in other patients. These differences can be clinically important, as immature blasts might have higher stemness capacity, a feature associated with poorer outcomes in AML. Conversely, blasts with monocytic differentiation may have immunosuppressive capacities, and relative BCL-2 independence. Previous reports based on bulk sequencing revealed only weak associations between NPM1/FLT3-ITD genotype and immature phenotype and between NPM1/FLT3-TKD or NPM1/RAS genotypes and monocytic/dendritic differentiation. Novel technologies allow simultaneous genotyping and analysis of surface protein expression at single-cell resolution and may help to resolve the interconnection between genotype and cell differentiation in leukemia. We used a droplet-based multi-omics single-cell platform to characterize the genetic clonal architecture in eleven NPM1-mutated AML diagnostic samples and investigate the relationship between co-mutations and phenotypic hematologic differentiation at the single-cell level.