Cone Precursor Cells Are the Cell-of-Origin in Retinoblastoma

Germline mutations in the RB1 gene are associated with a strong predisposition to the childhood retinal tumor retinoblastoma, suggesting that molecular pathways unique to a subpopulation of retinal cells may confer sensitivity to inactivation of this tumor suppressor. To test this hypothesis and characterize the potential cell-of-origin for retinoblastoma, Xu and colleagues depleted the RB protein in dissociated human fetal retinal cells, in purified retinal cell populations, and in intact retina. Loss of RB specifically enhanced the proliferation of postmitotic cone precursor cells but not retinal progenitor cells (RPC), rods, glia, or other retinal cell types. The sensitivity of cone precursors to RB depletion was associated with decreased apoptosis and increased expression of genes that regulate cell-cycle progression, whereas RB loss induced apoptosis in RPCs and glia. Similar to retinoblastoma cells, proliferation of RB-depleted cone precursors required expression of proteins highly expressed in this cell type, including NMYC, the E3 ubiquitin ligase MDM2, and markers of cone photoreceptor cells. Proliferation of both retinoblastoma cells and RB-deficient cone precursors was also dependent on the E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2) and SKP2-mediated degradation of the cyclin-dependent kinase inhibitor p27. In addition, knockdown of the RB-related protein p130 (encoded by RBL2), which is often lost in human retinoblastoma, or overexpression of p107 (encoded by RBL1), an RB-related protein highly expressed in human retinoblastoma, enhanced the proliferation of RB-depleted cone precursors, suggesting that these proteins have opposing functions in human retinal tumorigenesis. Depletion of RB and p130 in cone precursors promoted the formation of differentiated, highly proliferative retinoblastoma-like tumors in vivo, which were characterized by the expression of cone-specific proteins and the absence of DNA copy number alterations, analogous to human retinoblastoma. These findings implicate maturing cone precursors as the cell-of-origin for retinoblastoma and support the notion that cell-type–specific signaling selectively initiates tumor formation in these cells following RB1 inactivation.

Xu XL, Singh HP, Wang L, Qi DL, Poulos BK, Abramson DH, et al. Rb suppresses human cone–precursor–derived retinoblastoma tumours. Nature 2014 Sep 24 [Epub ahead of print].

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