A double-assurance mechanism restrains generation of high potential transit-amplifying progenitors during...

Stem cells can generate differentiated progeny directly or indirectly through transit-amplifying progenitors (TAPs), which are vulnerable to tumorigenic transformation. Despite clinical relevance, how stem cells regulate TAP production is unclear. Drosophila brains contain Asense+ stem cells (Type1 neuroblasts; T1NBs) that generate low neurogenic potential TAPs and Asense- stem cells (Type2 neuroblasts; T2NBs) that produce high-potential TAPs [Intermediate Neural Progenitors (INPs)]. Unexpectedly, cell-type-specific enhancers of genes essential for INP formation are poised in T1NBs despite never generating INP progeny. Thus, both NB types are competent to generate INPs. Inducing T1NBs to generate INPs is more efficient upon asense knockdown. The progeny of T2NBs expressing elevated Asense adopt a low-potential TAP identity instead of INPs. Elevated Asense expression limits tumor NB expansion driven by stalled INPs halting tumor expansion. We propose that a double-assurance mechanism characterized by dynamic superimposition of lineage-specific activators upon basal-state determinants defines NB capability to generate high-potential TAPs.