Potentially leukemogenic translocations can be found in normal individuals who do not go on to develop leukemia (9). Shown here are somatically mutated HSCs (black) in the context of normal bone marrow (normal HSCs are shown in gray) and in the bone marrow of a patient with an inherited bone marrow failure syndrome (genetically unfit HSCs are shown in red). The coefficient of selection for the somatically mutated HSC in normal hematopoiesis is low so the mutant HSC is not significantly more fit. However, when the large population of HSCs is genetically unfit, the same mutant clone has a better opportunity to gain a foothold. Here, the somatically mutated HSCs in the normal and abnormal hematopoietic states have precisely the same mutation. The somatic mutant HSC in the company of the genetically unfit HSCs has a higher selection coefficient, not because of an autonomous attribute, but because the surrounding stem cells are highly unfit. The unfit HSCs are purged from the bone marrow (t1) and are replaced by the progeny of the somatic mutant (this population expands at t2). The data reported in this issue of the JCI by Liu et al. (10) demonstrate that the truncation G-CSF receptor mutation is capable of influencing the expansion of HSCs in the context of G-CSF treatment in mice. Although key studies remain to be performed in human cells, the results do provide a likely pathophysiological mechanism (G-CSF–induced STAT5 activation via a conditionally mutated receptor) for clonal HSC expansion in patients with SCN, expansions that seem to be required very early in the leukemogenic process. t, time.