Defining the Relative Contribution of K27 Methylation and S31 Phosphorylation to Gliomagenesis in DIPG
Abstract
Diffuse intrinsic pontine gliomas (DIPG) are aggressive pediatric brain tumors occurring in the brain stem. They are a very rare form of cancer and almost always occur in young children, with approximately 200-300 new cases being reported annually in the United States. Their treatment is limited to surgical resection and radiotherapy. DIPG are among the most lethal of all human cancers; children diagnosed with DIPG typically live for less than a year. To date, no chemotherapeutic agent has shown any survival benefits in children with these tumors. The outcome of our work will be identifying how these brain tumors lead to discovering new drug targets and developing and validating a novel tumor-specific model that can also be used to support clinical trials. Thus, this work addresses two Fiscal Year 2021 Rare Cancers Research Program Focus Areas: Biology and Etiology – Identifying disease-defining molecular pathways, and Research Models – Developing and validating rare tumor-specific models that can support clinical trial readiness. Pediatric brain tumors are a serious problem affecting military Service Members and their families. The loss or suffering of a child can severely compromise a military Service Member s ability to perform and negatively impact their physiological well-being. Such circumstances likely harm a military unit s morale and cohesion. Ensuring Service Members and their families remain healthy is essential for a military unit s ability to carry out its critical function in our nation s defense. Genes control our bodies cells, forming a series of molecular instruction manuals for creating everything our cells need to grow, live, and function. The words in these instruction manuals are composed of DNA, a long molecular fiber that winds and unwinds for the cell to read these words. Our cells have 22,000 different instruction manuals, and the different cell types (nerve cells, muscle cells, bone cells, etc.) only use some of these words at a time-the rest remain silent (that way, a nerve cell does not become a bone cell, and a bone cell does not become a blood cell, etc.). DNA winds around histones, tiny spool-like proteins, to create structural units called nucleosomes. Nucleosomes, in turn, are wrapped into bigger fibers that form tightly packed chromatin, like a molecular yarn wound into a skein. Modifying histones regulates gene expression by relaxing or compacting chromatin and recruiting other components to silence or activate different genes (molecular words). Turning genes on and off to suit the particular cell is called epigenetic regulation. Histones are made up of pieces, like a long Lego toy, which are numbered by position. Different positions have varying functions in winding the DNA. Chemically modifying histone H3 at position 36 involves gene activation, whereas modifying histone H3 at position 27 is linked with gene silencing. Both position 27 and position 34 can be altered or mutated in DIPG (think different Lego colors); scientists call the change at position 27 H3.3 K27M mutations, and this alteration is a driving force behind DIPG. A chromosome is a long DNA molecule containing most of your genes. Healthy people typically have 23 pairs of chromosomes (46 in total). When a cell divides, all chromosomes must be duplicated, and both new daughter cells should have 23 pairs. Histones and alterations to them help regulate this process. Our proposed research contains the novel idea that the K27M and G34R mutations act as a double hit, not only interfering with epigenetic regulation but also causing chromosomes to divide improperly so that the daughter cells have the wrong number of chromosomes (chromosomal instability). Thus, genes that stop cells from growing become lost, and genes that promote growth are duplicated, causing cancer growth. We show that the improper changes in chromosome number are caused by a reduction of a different type of event known as ph
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211045
Entities
People
- James P. Robinson
Organizations
- United States Army
- University of Minnesota