title: A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells.
abstract: Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3+/Nestin+/Sox2+ population lining the fourth ventricle and a Pax3+/NeuN+ parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53(fl/fl) mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67+, Nestin+, Olig2+, and largely GFAP- and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease.
authors.affiliation: Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC. Electronic address: misuracak@gmail.com.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Misuraca
authors.affiliation: Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC. Electronic address: guo.hu@duke.edu.
authors.forename: Guo
authors.initials: G
authors.lastname: Hu
authors.affiliation: Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC. Electronic address: kell_barton@yahoo.com.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Barton
authors.affiliation: Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC. Electronic address: achung605@gmail.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Chung
authors.affiliation: Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC; Department of Pathology, Duke University Medical Center, Durham, NC. Electronic address: oren.becher@duke.edu.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
mesh_terms: D000818:Animals; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D000066630:Ectopic Gene Expression; D015870:Gene Expression; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism
chemical_list: D006657:Histones; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010982:Platelet-Derived Growth Factor; C068686:Pax3 protein, mouse