Coefficients of selection in normal bone marrow and in aplastic anemia. A hematopoietic stem cell (HSC) pool can reside in either a normal microenvironment (pathway arrow 1, “normal niche”) or within a hostile microenvironment (pathway arrow 2, “abnormal niche”). To emphasize the importance of the selection coefficient (low in pathway 1 and high in pathway 2), the pool of initially normal HSC contains one HSC with new alleles (bearing mutations of no consequence in the context of a normal niche). In the context of the hostile niche, the relative fitness of the same new alleles is massively amplified. Under the selective pressure of cytokines released by oligoclonal autoimmune T cells (“T”), the normal HSC are depleted over time (t1) and cytokine-resistant alleles are favored by selection because relative to the unfit wild-type stem cells, the mutant cells are much more fit. Under continued pressure from the aberrant T-cell population, the neoplastic clone preferentially expands over time (t2), while the less-fit normal HSC are selected against. In contrast, no evolution of the potentially neoplastic clone occurs in the supportive niche (pathway 1) because there is no selective pressure. That is, even though the phenotype of the mutant stem cell is the same as it was at the beginning of pathway 2, the fitness differences are not substantial enough to set the stage for clonal evolution. Not shown in this figure is a process by which a mutant stem cell arises in a population only after it is exposed to a hostile environment. This would meet strict genetic standards for an “adaptive mutation” in which the hostile environment per se induces mutations, some of which permit an adaptive response to the environment. The coefficient of selection idea would still be relevant here as well because relief of the environmental stress (e.g., effective immunotherapy of aplastic anemia) might lower the coefficient in time to prevent an outgrowth of adapted clonal progeny.