Leukemias are composed of a hierarchy of cells, only a fraction of which have stem cell–like properties and are capable of self‐renewal. Mixed lineage leukemia (MLL) fusion proteins produced by translocations involving the MLL gene on chromosome 11q23 confer stem cell–like properties on committed hematopoietic progenitors. This provides an opportunity to assess changes in immunophenotype, gene expression, and epigenetic programs during the transition from a hematopoietic cell with minimal inherent self‐renewal capability to cells capable of leukemic self‐renewal.