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 the gene 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-specific-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 p16 and 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 to inactivation and reveal the human cone precursors' capacity to model retinoblastoma initiation, proliferation, premalignant arrest, and tumor growth.

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

“…At the early clinical stages, the expression of RdCVF and RdCVFL mRNA can be measured using quantitative RT-PCR and the proteins by sandwich ELISA, but both requires the transduction of an immortalized cell line, cells that can be handled in a confined environment. Since RdCVFL is under control of a cone opsin promoter, only retinoblastoma cell lines that originate from cone precursors are expressing this transgene after their transduction with the AAV expressing RdCVF and RdCVFL [176]. At more advanced stages, the biological activities of both transgenes requires the development of tests after the transduction of the drug in such cell lines.…”

Temporal patterning in neural progenitors: from Drosophila development to childhood cancers

“…However, several observations suggest an important role. First, the fact that many pediatric CNS tumors can only be induced during very specific windows of development argues for the existence of temporal mechanisms regulating transient tumor-prone cellular states ( Han et al, 2016 ; Pathania et al, 2017 ; Singh et al, 2018 ). Second, as shown below, the comparison of single-cell transcriptomes from human and mouse developing brains with various pediatric CNS tumors supports the hypothesis that partial recapitulation of fetal transcription programs is a characteristic of CNS pediatric tumors.…”

A novel thyroid hormone receptor isoform, TRβ2-46, promotes SKP2 expression and retinoblastoma cell proliferation

“…Furthermore, the lack of TR␤2-46 in developing mouse retina (25,34) suggests that TR␤2-46 is not needed for cone development processes that are shared between mice and humans. Instead, TR␤2-46 may participate in human-specific processes such as foveagenesis or expression of a cone precursor proliferation-related program (2,3).…”

“…Retinoblastoma is a childhood retinal tumor that has provided insights into the role of cell type-specific circuitry in tumor initiation (1). Most retinoblastomas are thought to arise from cone photoreceptor precursors in response to biallelic inactivation of the RB1 gene and loss of functional RB protein (2,3). Human cone precursor circuitry may sensitize to RB1 mutation via intrinsic high expression of oncoproteins, such as MYCN and MDM2, and cone lineage transcription factors, such as retinoid X receptor-␥ (RXR␥) 3 and thyroid hormone receptor ␤2 (TR␤2) (2,4).…”

“…Most retinoblastomas are thought to arise from cone photoreceptor precursors in response to biallelic inactivation of the RB1 gene and loss of functional RB protein (2,3). Human cone precursor circuitry may sensitize to RB1 mutation via intrinsic high expression of oncoproteins, such as MYCN and MDM2, and cone lineage transcription factors, such as retinoid X receptor-␥ (RXR␥) 3 and thyroid hormone receptor ␤2 (TR␤2) (2,4). RXR␥ and TR␤2 normally mediate cone photoreceptor differentiation (5,6) but promote cone precursor proliferation and retinoblastoma genesis after RB loss (2,4).…”