Abstract
Abstract A recent exome sequencing study of pancreatic neuroendocrine tumors (PanNETs) provided valuable information about the genetic landscape of these cancers and for the first time implicated DAXX and ATRX loss in tumorigenesis. These interacting proteins are chaperones for the histone variant H3.3 and contribute to chromatin homeostasis and telomere maintenance. Mutually exclusive mutations in DAXX or ATRX occur in 43% of PanNETs. To understand how loss of these epigenetic regulators specifically contributes to tumorigenesis, we are developing genetically engineered mouse models of PanNETs. While a mouse with a conditional Daxx allele is publically available, subsequent sequencing and characterization revealed a mutant loxP site, which renders recombination extremely inefficient. We are, therefore, currently generating a new conditional Daxx allele, as well as using an existing conditional Atrx allele to specifically delete these genes in the endocrine pancreas. Cohorts of mice are being built and followed for developmental and tumor phenotypes. In addition, in vitro studies have also implicated a role for DAXX as a negative regulator of the p53 tumor suppressor pathway. Interestingly, p53 is rarely mutated in PanNETs. We are using a Daxx-null allele, generated using the existing conditional Daxx mouse, to investigate the relationship between DAXX and the p53 pathway in vivo. Combined, this work aims to generate and characterize mouse models which will lead to a better understanding of both the etiology of PanNETs and how loss of DAXX and ATRX contribute to tumorigenesis. Note: This abstract was not presented at the meeting. Citation Format: Amanda R. Wasylishen, Guillermina Lozano. Understanding the mechanisms driving pancreatic neuroendocrine tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3917. doi:10.1158/1538-7445.AM2014-3917
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
