title: Rb suppresses human cone-precursor-derived retinoblastoma tumours.
abstract: Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear. Here we show that post-mitotic human cone precursors are uniquely sensitive to Rb depletion. Rb knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN and MDM2. Proliferation of Rb-depleted cones and retinoblastoma cells also depended on the Rb-related protein p107, SKP2, and a p27 downregulation associated with cone precursor maturation. Moreover, Rb-depleted cone precursors formed tumours in orthotopic xenografts with histological features and protein expression typical of human retinoblastoma. These findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. More generally, they demonstrate that cell-type-specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis.
authors.affiliation: 1] Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA [2] Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
authors.forename: Xiaoliang L
authors.initials: XL
authors.lastname: Xu
authors.affiliation: 1] The Vision Center, Division of Ophthalmology, Department of Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA [2] The Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA.
authors.forename: Hardeep P
authors.initials: HP
authors.lastname: Singh
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1] The Vision Center, Division of Ophthalmology, Department of Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA [2] The Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA.
authors.forename: Dong-Lai
authors.initials: DL
authors.lastname: Qi
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Bradford K
authors.initials: BK
authors.lastname: Poulos
authors.affiliation: Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Abramson
authors.affiliation: 1] Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA [2] Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Jhanwar
authors.affiliation: 1] The Vision Center, Division of Ophthalmology, Department of Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA [2] The Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California 90027, USA [3] USC Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, 1450 San Pablo Street, Los Angeles, California 90033, USA [4] Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, 1441 Eastlake Avenue, Los Angeles, California 90033, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cobrinik
mesh_terms: D002471:Cell Transformation, Neoplastic; D050684:E2F Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma / Q000235:genetics; D064593:Heterografts; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D009928:Organ Specificity; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology*; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000172:deficiency / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D050684:E2F Transcription Factors; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C493844:RBL1 protein, human; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D044786:S-Phase Kinase-Associated Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2