Elucidating the role of PATZ1 in MYCN-amplified neuroblastoma

Project Summary Neuroblastoma is the most common extra-cranial cancer that affects children, accounting for approximately 15% of childhood cancer deaths. Children are typically diagnosed with neuroblastoma under the age of 5 years old with an average of between 1-2 years of age. MYCN-amplified neuroblastoma comprises approximately 20-25% of all neuroblastoma cases, has a 5-year survival rate of approximately 50%, and it is associated with therapy resistance and lower survival rates. Despite improvements in the five-year survival rate for high-risk neuroblastoma, current therapies are aggressive and negatively impact the quality of life for patients with neuroblastoma. Therefore, there is an urgent need to develop novel therapies that improve both the mortality and morbidity rates of patients with neuroblastoma. Using the Broad Institute’s Dependency Map (DepMap), I identified PATZ1 (POZ/BTB and AT Hook Containing Zinc Finger 1) as a selective and potentially druggable dependency in neuroblastoma. Currently, the role of PATZ1 in cancer has varying reports as both a possible tumor suppressor and oncogene, and further investigation is needed to elucidate the role of PATZ1 in tumorigenesis and tumor cell maintenance. My preliminary data has confirmed that neuroblastoma cells have decreased viability after PATZ1 knockout using CRISPR Cas9 technology. In addition, preliminary CUT&RUN and ChIP- seq analysis suggests that PATZ1 binds coordinately with members of the core regulatory circuitry (CRC), including MYCN, to regions of open chromatin marked by enhancers. The CRC is responsible for regulating the cell fate of neuroblastoma, leading me to hypothesize that PATZ1 plays a critical role in maintaining the oncogenic cell state of neuroblastoma. In this proposal, Aim 1 will assess PATZ1 as a potential therapeutic target in neuroblastoma by rigorously testing the effect of PATZ1 knockout and degradation both in vitro and in vivo. To elucidate the mechanism of action of PATZ1 dependency in neuroblastoma, Aim 2 will evaluate the transcriptional and epigenetic consequences of PATZ1 knockout and degradation in neuroblastoma cell lines. This work will validate a new druggable dependency in neuroblastoma and expand our understanding of epigenetic factors driving the oncogenic cell state of neuroblastoma.