Brain tumors are the leading cause of cancer-related deaths in children. Glioblastoma multiforme (GBM) is a deadly form of brain cancer that strikes both children and adults. Children diagnosed with GBM face dismal outcomes. Even aggressive treatment strategies are ineffective, as less than 20% of children will survive more than three years post-diagnosis. Sequencing of pediatric GBM has identified concurrent mutations in the genes encoding an ATP-dependent chromatin remodeling enzyme called ATRX, in p53, and in the histone variant, H3.3 (encoded by H3F3A and H3F3B). In cancer, ATRX mutations result in a loss of ATRX expression or activity and correlate with genome instability, aberrant telomere and centromere phenotypes, and with poor clinical prognosis. H3.3 mutations are found in the histone tail region that is subject to extensive covalent modification. Forced expression of mutant H3.3 has been recently shown to act in a dominant manner to induce global changes in the methylation of chromatin, yet the functional consequences of these mutations are still poorly understood. Based on these findings, we will test the overall hypothesis that ATRX and H3.3 mutations act in a cooperative manner leading to epigenetic instability, centromere and telomere abnormalities, and GBM tumorigenesis. First, we will generate novel mouse models of brain cancer to mimic the effects of patient ATRX and H3.3 mutations, which will be made available to the scientific community for future studies testing whether certain drugs can inhibit the growth of these tumors. In parallel, we will investigate the consequences of ATRX and H3.3 mutations on a mechanistic level. Using cutting edge microscopy and sequencing techniques we will analyze changes in DNA and chromatin organization after forcing normal neural progenitor cells to have ATRX and H3.3 mutations. We will also purify ATRX and both normal and mutant forms of H3.3 and study how these factors might work together to re-organize DNA into chromatin in a test tube. We hope that the detailed understanding of the functions of ATRX and H3.3 in mediating chromatin organization gained from these studies will enable the development of personalized therapies for cancer patients suffering from brain tumors with ATRX and H3.3 mutations.

Public Health Relevance

The current treatment strategies have failed children diagnosed with malignant glioblastoma, a deadly form of brain cancer, as less than 20% of patients will survive more than 3 years post-diagnosis despite aggressive treatment combining surgery, chemotherapy and radiation. The overall goal of this research proposal is to determine if and how different combinations of mutations can lead to brain tumor development. Ultimately, these studies may inform the development of alternative therapies for pediatric brain cancer.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA189741-01
Application #
8784425
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcguirl, Michele
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115