Developmental stage-specific proliferation and retinoblastoma genesis in RB-deficient human but not mouse cone precursors

Abstract

Most retinoblastomas initiate in response to the inactivation of theRB1gene and loss of functional RB protein. The tumors may form with few additional genomic changes and develop after a premalignant retinoma phase. Despite this seemingly straightforward etiology, mouse models have not recapitulated the genetic, cellular, and stage-specific features of human retinoblastoma genesis. For example, whereas human retinoblastomas appear to derive from cone photoreceptor precursors, current mouse models develop tumors that derive from other retinal cell types. To investigate the basis of the human cone-specific oncogenesis, we compared developmental stage-specific cone precursor responses to RB loss in human and murine retina cultures and in cone-specificRb1-knockout mice. We report that RB-depleted maturing (ARR3+) but not immature (ARR3−) human cone precursors enter the cell cycle, proliferate, and form retinoblastoma-like lesions with Flexner–Wintersteiner rosettes, then form low or nonproliferative premalignant retinoma-like lesions with fleurettes and p16INK4Aand p130 expression, and finally form highly proliferative retinoblastoma-like masses. In contrast, in murine retina, only RB-depleted immature (Arr3−) cone precursors entered the cell cycle, and they failed to progress from S to M phase. Moreover, whereas intrinsically highly expressed MDM2 and MYCN contribute to RB-depleted maturing (ARR3+) human cone precursor proliferation, ectopic MDM2 and Mycn promoted only immature (Arr3−) murine cone precursor cell-cycle entry. These findings demonstrate that developmental stage-specific as well as species- and cell type-specific features sensitize toRB1inactivation and reveal the human cone precursors’ capacity to model retinoblastoma initiation, proliferation, premalignant arrest, and tumor growth.