Abstract
Abstract Retinoblastomas initiate in response to biallelic RB1 inactivation and loss of functional Rb protein, yet the cell of origin and cellular circuitry that sensitizes to Rb loss have been unclear. Here, we probed the cellular origin of retinoblastoma by assessing cell type-specific responses to shRNA-mediated Rb depletion in dissociated fetal retina, in intact retina, and in isolated cone precursor populations. In dissociated retinal cultures, RB1 knockdown induced S phase entry and proliferation of cells expressing markers of cone precursors (CRX + L/M opsin, or CRX + cone arrestin, or CRX + RXRγ) but not markers or other retinal cell types. Similarly, RB1 knockdown induced cone precursor proliferation in the undissociated retina and in prospectively isolated cone precursor populations. Proliferation of FACS-isolated cone precursors correlated with the induction of E2F-responsive genes and depended upon factors having strong cone precursor expression and crucial roles in retinoblastoma cell proliferation, including MDM2, MYCN, TRβ2, and SKP2. The proliferative response to Rb depletion was enhanced by co-depletion of the Rb-related p130 but was abrogated by co-depletion of p107, concordant with frequent p130 but not p107 losses in retinoblastoma tumors. Rb- and Rb/p130-depleted cone precursors proliferated in suspension and formed tumors in orthotopic xenografts with histologic features and protein expression profiles typical of differentiated human retinoblastomas. These findings indicate that post-mitotic human cone precursors are uniquely sensitive to the proliferative and oncogenic effects of Rb depletion and imply that human cone precursor circuitry collaborates with inactivating RB1 mutations to initiate retinoblastoma tumorigenesis. Citation Format: Xiaoliang L. Xu, Hardeep P. Singh, Lu Wang, Donglai Qi, Bradford K. Poulos, David H. Abramson, Suresh C. Jhanwar, David Cobrinik. Human cone precursor-derived retinoblastoma tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-39. doi:10.1158/1538-7445.AM2014-LB-39
Published Version
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