Model of HSC clonal evolution leading to MDS and AML pathogenesis and progression. Schematic depiction of a hypothetical evolutionary history in the stem compartment and its representation in bulk samples. Clonal evolution begins with the acquisition of mutations or other nongenetic aberrations that result in clonal expansion and further mutation of the founder clone. A descendent HSC may gain a new aberration, causing it to branch into a new subclone. Branching subclones continue to evolve in parallel and may have disparate responses to selective pressures. Some subclones expand rapidly upon acquisition of a new mutation, whereas others may remain stable for longer periods. Extrinsic pressures, such as targeted therapies, may affect only some clones, whereas nontargeted therapies may have a more widespread, but often also less deep, effect. Clonal outgrowth is represented with time on the x-axis and relative abundance of HSC clones on the y-axis. The colors represent accumulated aberrations. The lower panels show the relative frequency of each alteration found in the bulk blood population at selected time points. Bulk sampling may not reflect the complete diversity and complexity found in HSCs, because variants below the detection limit (dotted line) will not be accounted for but may be shown to be disease relevant at later time points.