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 Edward H. Hinchcliffe, PhD
 “Understanding basic science behind
diffuse midline gliomas in children.”
Edward H. Hinchcliffe
34 | THE HORMEL INSTITUTE Cellular Dynamics
ASSISTANT DIRECTOR FOR EDUCATION / PROFESSOR
// UNIVERSITY OF MINNESOTA
  Our lab works to understand the cell and molecular basis for tumorigenesis, in particular pediatric brain tumors. We
study mitosis, the process where cells separate duplicated chromosomes into two daughter cells. Mistakes in mitosis lead to uneven chromosome segregations, a hallmark of cancer progression. We study how single changes (mutations) in DNA can lead to chromosome missegregation following mitosis. By understanding the basic mechanisms underlying these cellular defects, we will identify therapeutic targets to treat these patients in the clinic.
Pediatric Brain Tumors
Pediatric glioblastomas are high-grade child- hood brain tumors that are infiltrative, resistant to conventional therapies, and carry a dismal prognosis, with 5-year survival rates well below 10%. Pediatric glioblastomas, particularly diffuse intrinsic pontine glioma (DIPG), are clinically and biologically distinct from the adult disease and defined in part by highly specific heterozygous mutations K27M (or G34R) in the genes that encode histone H3, primarily in the variant H3.3. Methylation of a key lysine residue (Lys27) on H3 acts as an epigenetic regulator. Loss of Lys27 tri- ple methylation (Me3) – caused by the dominant
negative K27M mutation – reprograms the epigenome and is proposed as a driving event in pediatric gliomas.
Our recent work suggests that K27M (or G34R) also contribute to tumorigenesis
via inhibition of Ser31 phosphorylation and the induction of chromosome instability. In histone H3.3, Ser31 is one of five amino acid substitu- tions that differentiate it from canonical H3.1. H3.3 Ser31 is phosphorylated during mitosis specifically at pericentromeric heterochromatin, where it plays a role in chromosome segregation. We find that K27M or G34R mutations inhibit H3.3 Ser31 phosphorylation in vitro. Pediatric DIPG cell lines with the K27M mutation exhibit
a significant decrease in Ser31 phosphorylation in vivo, and that these cells exhibit chromosome instability. CRISPR-Cas9 editing of the K27M mu- tation (H3.3M27K) restores WT levels of Ser31 phosphorylation during mitosis, and revertants show significant decreases in chromosomal instability. These revertants also regain WT levels of Lys27 triple methylation. In diploid cells, ex- pression of K27M, G34R, or S31A non-phosphor- ylatable mutant triggers chromosome instability.
      



















































































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