Fig. 9. Knockdown of trx and PRC2 genes impairs temporal progression at the top of the tumor hierarchy.

(A) NB tumors induced by the loss of pros exhibit a strict hierarchical organization governed by the recapitulation of larval temporal patterning. trx inactivation in pros^RNAi tumors promotes temporal reversion and the appearance of Imp⁺ tNBs with an embryonic temporal identity (D⁺Cas⁺Grh⁻) in adult tumors. The embryonic temporal identity is reinforced upon coinactivation of trx and E(z). (B) During development, NBs are subjected to a hierarchy of temporal/developmental states likely partly guided by an epigenetic landscape. During pros^RNAi-mediated tumorigenesis, larval temporal patterning is coopted and induces a cellular hierarchy. Inactivation of trx flattens the epigenetic landscape at the top of the tumor hierarchy. This leads to temporal reversion and emergence of a tNB population with an embryonic-like temporal identity (D⁺Cas⁺Grh⁻) at the top of the hierarchy. Embryonic Imp⁺ tNBs are less inclined to progress toward the late steps of the hierarchy. Flattening of the epigenetic landscape at the top of the hierarchy is worsened by the coinactivation of PRC2 genes, locking Imp⁺ tNBs into a spectrum of CSC states. Our work suggests that trx and PRC2 genes are essential regulators of the epigenetic landscape guiding temporal progression at the top of the tumor hierarchy.