Clonal architecture and genetic heterogeneity. The normal bone marrow contains a heterogeneous mixture of equally represented HSC clones. Each normal HSC clone accumulates a unique set of passenger mutations throughout its lifespan, defining a clonal genetic mosaicism of normal hematopoiesis that is undetectable by bulk sequencing analysis. When 1 clone acquires a driver mutation that causes a selective growth advantage, depicted with a red circle, the progeny of this mutated cell gain clonal dominance and may cause clinically apparent disease. Within this dominant clone, additional mutations can cooperate to drive further clonal advantage, illustrated with darker red circles, and define genetically distinct subclones. Upon treatment, a myeloid malignancy can be driven into remission, although the persistence of any residual disease clones can serve as the substrate for relapse, potentially bearing a new mutation, depicted in blue.