Diffuse intrinsic pontine gliomas (DIPGs) are deadly tumors comprising 10-15% of all childhood central nervous system (CNS) cancers. Standard treatment consists of focal radiation which results in only transient response. Given the increasing promise of immunotherapy, there have been ongoing genomic and proteomic efforts to identify robust, tumor specific antigens to serve as immunotherapy targets.
Here, we explore Wilms’ tumor protein (WT1) as a tumor associated antigen in DIPG and potential oncogenic role of WT1 in tumorigenesis and progression of this intractable disease. DIPGs have recently been classified into genomic subtypes based on histone variants with the lysine to methionine mutation on position 27 of histone tails (K27M). Intriguingly, WT1 expression was found to be highly correlated with oncohistone variants and was specifically associated with oncohistone H3.3. WT1 expression was absent in all adjacent normal tissues, increasing its potential as a suitable immunotherapeutic target. Our in-vitro and in-vivo investigation on the effects of WT1 overexpression in human DIPG cells and murine models generated from orthotopic injections of these cells suggested WT1 as an oncogene in DIPGs. Our data are the first indication of WT1 association with DIPGs with specific upregulation in those harboring oncohistone H3.3 and demonstrating an oncogenic role in DIPGs. Our results have the potential to accelerate the discovery of novel therapeutic interventions for children diagnosed with DIPG.
|Advisor:||Nazarian, Javad, Vilain, Eric|
|Commitee:||Tzatsos, Alexandros, Cruz, Conrad|
|School:||The George Washington University|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 82/3(E), Dissertation Abstracts International|
|Keywords:||Diffuse intrinsic pontine gliomas, Tumor specific antigens, Childhood central nervous system|
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