The leukemic state and disease progression. (A) Topology of normal hematopoietic differentiation with the “leukemic state” as a trapped basin in gene expression space. (B) Two models of therapeutic resistance in AML. In the genetic scenario, acquisition of resistance mutations (denoted with R+) in a polyclonal malignancy creates a selective pressure that leads to AML relapse. In the transcriptional state plasticity scenario, cells can occupy a diversity of cellular microstates within the “leukemic state” that make them more or less susceptible to clearance by chemotherapy. If these states are based on the expression of particular TF, then selected states could be inherited in relapse tumors. Importantly, these mechanisms are likely not mutually exclusive and are intrinsically dependent on one another.