Retinoblastoma is a malignant pediatric tumor in which mutations in the RB gene occur in the vast majority of cases. While retinoblastoma is initiated by RB inactivation, the steps between RB loss and tumorigenesis are not well understood. This proposal aims to investigate the changes that occur as retinoblastomas initiate and progress to malignancy. Mechanisms of cooperation with RB deletion in retinoblastoma may be broadly relevant for many human cancers. I hypothesize that secondary alterations help the retinoblastoma cell of origin evade a pathway to cell cycle exit controlled by the Rb family member, p130. These secondary alterations may alter the activity of p130 through control of cyclin dependent kinases (CDKs) or may act at other points in the pathway (e.g. by regulating E2F transcription factors). Moreover, I hypothesize that evasion of p130-controlled cell cycle exit in RB-deficient cells may be important not only for retinoblastoma, but for other tumor types. To test these hypotheses, we will use a combination of mouse genetics, cell culture studies and investigation of primary human and murine tumor samples. These studies will use the power of mouse models to determine definitively whether candidate Rb-cooperating genes are important for tumorigenesis and to understand how these co-operating genes synergize with Rb loss.
Specific Aim 1 : Investigate the mechanism by which Arf functions as tumor suppressor gene in retinoblastoma.
Specific Aim 2 : Assess whether N-myc alters the activity of the pRB family members in promoting tumorigenesis. This work has important implications for understanding many human tumor types that exhibit RB pathway inactivation. If pathways controlled by RB family members are functionally inactivated through secondary alterations, then reactivation of such pathways may provide new opportunities for therapeutic intervention.

Public Health Relevance

The RB gene is deleted in many human tumors and the RB pathway is disrupted in virtually every human cancer. Certain cells in the developing retina are exquisitely sensitive to retinoblastoma upon RB gene mutation making retinoblastoma an ideal system to understand mechanisms behind cooperation with RB loss in tumorigenesis. We use mouse models and studies of human retinoblastoma samples to learn how RB- cooperating genes contribute to cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Hildesheim, Jeffrey
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Carnegie Institution of Washington, D.C.
United States
Zip Code
Wu, Nan; Jia, Deshui; Bates, Breanna et al. (2017) A mouse model of MYCN-driven retinoblastoma reveals MYCN-independent tumor reemergence. J Clin Invest 127:888-898
Augert, Arnaud; Zhang, Qing; Bates, Breanna et al. (2017) Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance). J Thorac Oncol 12:704-713
Kim, Dong-Wook; Wu, Nan; Kim, Young-Chul et al. (2016) Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer. Genes Dev 30:1289-99
Cui, Min; Augert, Arnaud; Rongione, Michael et al. (2014) PTEN is a potent suppressor of small cell lung cancer. Mol Cancer Res 12:654-9
Conkrite, Karina; Sundby, Maggie; Mu, David et al. (2012) Cooperation between Rb and Arf in suppressing mouse retinoblastoma. J Clin Invest 122:1726-33
Conkrite, Karina; Sundby, Maggie; Mukai, Shizuo et al. (2011) miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma. Genes Dev 25:1734-45