Retinoblastoma
 

Retinoblastoma (RB) is the most common intraocular tumor in children, triggered by biallelic mutations in the RB1gene or amplification of the MYCNoncogene. RB can be unilateral (60%-70%) or bilateral (30%-40%). Bilateral tumors are typically hereditary and present at an earlier age. Retinoblastoma accounts for 2% to 4% of childhood malignancies and is a common primary tumor of the eye. The global incidence in newborns is approximately 1 in 16,000.
 

Pathogenesis
 

The core pathogenesis of retinoblastoma involves the biallelic inactivation of the RB1tumor suppressor gene. In heritable cases, patients carry a germline mutation in one RB1allele, with the other allele undergoing somatic inactivation during retinal development. In sporadic cases, two consecutive somatic mutations must occur within the same retinal cell. The pRb protein encoded by RB1is a key regulator of the G1/S cell cycle checkpoint. Through its conserved pocket domain, it binds to E2F transcription factors (primarily E2F1-E2F3) and recruits chromatin-modifying complexes such as histone deacetylases to form a transcriptional repression complex, thereby inhibiting the expression of cell cycle-related genes. Inactivation of RB1leads to constitutive activation of E2F, resulting in uncontrolled cell cycle proliferation and the formation of tumor precursors.
 

Isolated RB1inactivation often leads to benign retinoma, and its progression to malignancy requires the accumulation of additional genetic alterations. MYCNgene amplification is a key cooperative event, driving proliferation and inhibiting differentiation and apoptosis through a dose effect, which is closely associated with invasion and metastasis. Chromosomal instability leads to aneuploidy such as 1q gain, 6p gain, and 16q loss, further disrupting the balance of gene expression. High-grade tumors commonly exhibit events like TP53mutations (apoptosis escape), PTENdeletion (activating the PI3K/AKT pathway), and BCORmutations (epigenetic dysregulation), collectively enhancing cell survival, genomic instability, and treatment resistance. Epigenetic abnormalities, such as hypermethylation of genes like KDM6B, are also involved in differentiation blockade and malignant progression.
 

Image source: "RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis"
 

Mouse Models
 

Rb1 KO Mice:​ These mice have a complete loss of Rb1gene function. Homozygous embryos die during mid-gestation due to severe defects in nervous and hematopoietic system development. This model is primarily used to study the critical role of the Rb1gene in embryonic development and to validate its function as a tumor suppressor gene.
 

MYCN Overexpression Mice:​ These mice specifically overexpress the MYCNproto-oncogene in retinal photoreceptor precursor cells. Their key feature is the ability to independently induce retinoblastoma in the absence of Rb1mutations. This model is mainly used to explore the MYCNoncogenic signaling network and to evaluate the efficacy of drugs targeting MYCN.
 

Conditional Rb Knockout Mice:​ These models enable the knockout of the Rb1gene in specific cell types (e.g., retinal progenitor cells) and at specific time points, allowing control over the spatiotemporal location of tumorigenesis. They are primarily used for in-depth study of the cellular origin of tumors and to uncover early molecular events following Rb1loss.
 

Support
 

Gene therapy brings hope for rare diseases, but its development and validation are inseparable from the support of animal models. MingCeler Biotech, leveraging its self-developed TurboMice™ technology, has developed several rare disease mouse models. TurboMice™ technology overcomes the technical challenges of long modeling cycles and low success rates for complex models, enabling editing at nearly any target gene locus. It can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech​ can customize various RB mouse models according to client needs, such as Rb1 KO mice, MYCN overexpression mice, and conditional Rb knockout mice. Inquiries are welcome.
 

References:
 

1.Zhou Yuan, Li Cairui. Research progress on the epigenetic mechanisms of retinoblastoma[J]. Chinese Journal of Ocular Fundus Diseases, 2025, 41(07): 566-571. DOI:10.3760/cma.j.cn511434-20250217-00057

2.Di Fiore R, D'Anneo A, Tesoriere G, Vento R. RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis. J Cell Physiol. 2013 Aug;228(8):1676-87. doi: 10.1002/jcp.24329. PMID: 23359405.

3.Knudsen ES, Pruitt SC, Hershberger PA, Witkiewicz AK, Goodrich DW. Cell Cycle and Beyond: Exploiting New RB1 Controlled Mechanisms for Cancer Therapy. Trends Cancer. 2019 May;5(5):308-324. doi: 10.1016/j.trecan.2019.03.005. Epub 2019 Apr 30. PMID: 31174843; PMCID: PMC6719339.

4.Huang MF, Wang YX, Chou YT, Lee DF. Therapeutic Strategies for RB1-Deficient Cancers: Intersecting Gene Regulation and Targeted Therapy. Cancers (Basel). 2024 Apr 19;16(8):1558. doi: 10.3390/cancers16081558. PMID: 38672640; PMCID: PMC11049207.

5.Wu N, Jia D, Bates B, Basom R, Eberhart CG, MacPherson D. A mouse model of MYCN-driven retinoblastoma reveals MYCN-independent tumor reemergence. J Clin Invest. 2017 Mar 1;127(3):888-898. doi: 10.1172/JCI88508. Epub 2017 Feb 6. PMID: 28165337; PMCID: PMC5330763.