Schematic illustrating the effects of AC220 on MPPs and the Flt3 ligand–associated recovery response. Over the first 4 days of treatment, AC220 promotes quiescence of MPPs, resulting in a marked reduction in their numbers and the expression of Flt3 receptors (illustrated by the small noncycling cells on day 4 with fewer Flt3 receptors). We propose that the loss of MPPs and the reduction of Flt3 expression during these first 4 days are detected by the BM stromal cells, possibly through fewer interactions with membrane-bound Flt3 ligand. This triggers a strong signal that results in the stromal cells markedly increasing their production of Flt3 ligand (red arrows). The resultant robust response by Flt3 ligand then restores the proliferative capacity of the MPPs. From our data shown in Figure 5, it can be seen that the proliferative response on day 8 is even stronger than that seen in c-Cbl RING finger mutant mice that were not treated with AC220 (illustrated by their larger size and the larger cycling arrows). Beyond this point, a steady state is established in which the proliferation driven by high levels of Flt3 ligand is kept in check by the inhibitory effects of AC220, the net effect being that the numbers of MPPs do not increase beyond the initial reduction that occurred during the first 4 days of treatment.