Modes of evolution from clonal hematopoiesis to malignant transformation. In the presence of high exogenous or endogenous G-CSF, subclones with truncating CSF3R variants have a competitive advantage and expand over time. With continued pressure from excessive G-CSF signaling, cooperating RUNX1 variants (*) can contribute to malignant transformation. In SDS, ribosome biogenesis stress selects for subclones that have adapted through acquisition of EIF6 or TP53 somatic variants. Chronic ribosome biogenesis stress can lead to either continued adaptive clonal hematopoiesis or, in TP53 subclones clones that have acquired a second TP53 variant on the other allele, malignant transformation.