Developing a clinically-relevant genetically engineered mouse model for Nut carcinoma

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Title: Developing a Clinically-Relevant Genetically Engineered Mouse Model of NUT Carcinoma Project Summary: A testis-specific gene called Nuclear protein in testis (NUTM1) has emerged as a recurrent fusion partner of oncogenic fusion genes in poorly understood neoplasms. Among these neoplasms, NUT carcinoma (NC) is the most aggressive and is the paradigm for the study of NUTM1 fusion gene-associated cancers. The majority of NCs are associated with a chromosome translocation that joins together gene fragments of the Bromodomain- containing protein 4 (BRD4) and the NUTM1 protein. Clinical research and experimental research based on in vitro cell culture systems has established the BRD4-NUTM1 fusion protein as the sole driver of NC. This project will address two vital current issues in NC research: Issue 1: Paradoxically, although BRD4-NUTM1 suffices to drive NC, ectopic expression of BRD4-NUTM1 in non-NC cells is unequivocally cytotoxic. Whether there is a specific cell type in which NCs originate — and how these cells are able to circumvent the cytotoxic effects of BRD4-NUTM1 — is a mystery. Issue 2: As the driver of NC oncogenesis, BRD4–NUTM1 is the most promising drug target for treating NC. However, targeted therapy strategies directed against the BRD4 fragment of BRD4-NUTM1 have been disappointing, largely because of intolerable side effects that are due to endogenous BRD4 being broadly expressed. Targeting the testis-specific NUTM1 protein has the potential to circumvent most systematic side effects in male patients and all side effects in female patients, yet this strategy has not been explored in a physiological context. Building on our expertise in genome editing technology and unique resources in genetically engineered mouse lines, we will address these two vital NC issues by building the first genetically engineered mouse model that can recapitulate the tissue and physiological context of NC. Aim 1 will build and characterize an inducible chromosome translocation mouse model for NC. Our model mice will express reporter genes for tracing and isolating NC cells that express BRD4-NUTM1. Aim 2 will identify the NC cell type of origin by analyzing genomic data from NC-originating normal cell populations and cells in early stages of NC development. Aim 3 will leverage in vivo inducible BRD4-NUTM1 protein degradation to model NUTM1 targeting in order to establish a targeting strategy for treating NC with minimal side effects. Overall Impact. This project will produce a genetically engineered mouse model of Nut Carcinoma as an entirely new experimental tool for studying oncogenic mechanisms of BRD4-NUTM1. Our studies will transform understanding of early-stage NC and spur therapeutic development to treat NC without intolerable side effects. This project will also shed light on mechanisms and treatment strategies for other poorly understood cancers with NUTM1 fusion genes.