Figure 5.
Addition of a defector clone (CD) results in decline of fitness of a malignant clone (CM) but stable coexistence with a benign clone (CB). With aging and various other insults, the leukemic microenvironment is transformed, no longer resembling the greater tissue architecture of healthy bone marrow. In the absence of therapy, this aberrant microenvironment may possess growth signals and disrupted tissue organization such that a malignant clone bears a fitness advantage (left). Upon administration of cellular therapy, a defector cell enters the fitness landscape, depleting microenvironmental nutrients critical for sustaining the highly proliferative malignant clone, and, thereby, altering the entire fitness landscape (right). The outcome of this therapy is a stable coexistence of defector cells and benign clones capable of sustaining hematopoiesis. Of note, this depiction differs slightly from previous figures and Wright's classic fitness landscape, as clones are more loosely defined as traveling across phenotypic space, which encompasses both genetic and nongenetic (including transcriptional and epigenetic) components. Within a given population of genetically identical (clonal) cells, there exists subpopulations of cells exhibiting varying transcriptional states that will contribute to clonal evolution and ultimately dictate phenotype.