Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells

Yishai Avior, Elyad Lezmi, Dorit Yanuka, Nissim Benvenisty

Research output: Contribution to journalArticlepeer-review


Human embryonic stem cells (hESCs) provide a platform for studying human development and understanding mechanisms underlying diseases. Retinoblastoma-1 (RB1) is a key regulator of cell cycling, of which biallelic inactivation initiates retinoblastoma, the most common congenital intraocular malignancy. We developed a model to study the role of RB1 in early development and tumor formation by generating RB1-null hESCs using CRISPR/Cas9. RB1−/− hESCs initiated extremely large teratomas, with neural expansions similar to those of trilateral retinoblastoma tumors, in which retinoblastoma is accompanied by intracranial neural tumors. Teratoma analysis further revealed a role for the transcription factor ZEB1 in RB1-mediated ectoderm differentiation. Furthermore, RB1−/− cells displayed mitochondrial dysfunction similar to poorly differentiated retinoblastomas. Screening more than 100 chemotherapies revealed an RB1–/–-specific cell sensitivity to carboplatin, exploiting their mitochondrial dysfunction. Together, our work provides a human pluripotent cell model for retinoblastoma and sheds light on developmental and tumorigenic roles of RB1.

Original languageAmerican English
Pages (from-to)1354-1365
Number of pages12
JournalStem Cell Reports
Issue number5
StatePublished - 9 May 2017


  • RB1
  • ZEB1
  • disease modeling
  • human embryonic stem cells
  • trilateral retinoblastoma

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology


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