title: Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.
abstract: High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis.
authors.affiliation: Graduate Program in Molecular Cancer Biology, Duke University, Durham, NC, USA. kml11@duke.edu.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Misuraca
authors.affiliation: Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC, USA. kell_barton@yahoo.com.|Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. 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, USA. achung605@gmail.com.|Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. achung605@gmail.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Chung
authors.affiliation: Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA. Alex.Diaz@stjude.org.|Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Alex.Diaz@stjude.org.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Diaz
authors.affiliation: Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. siconway@iu.edu.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.affiliation: Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA. david.corcoran@duke.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Corcoran
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Suzanne.Baker@stjude.org.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Baker
authors.affiliation: Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC, USA. oren.becher@duke.edu.|Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. oren.becher@duke.edu.|Department of Pathology, Duke University Medical Center, Durham, NC, USA. oren.becher@duke.edu.|Department of Pediatrics, Duke University Medical Center, 450 Research Drive, Durham, NC, 27710, USA. oren.becher@duke.edu.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001933:Brain Stem / Q000503:physiopathology; D020295:Brain Stem Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D063646:Carcinogenesis / Q000378:metabolism*; D002460:Cell Line; D002540:Cerebral Cortex / Q000503:physiopathology; D002645:Chickens; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000503:physiopathology; D064231:Nestin / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D008222:Lymphokines; C577485:Nes protein, mouse; D064231:Nestin; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C068686:Pax3 protein, mouse