TY - JOUR
T1 - The transcription factor Olig2 is important for the biology of diffuse intrinsic pontine gliomas
AU - Anderson, Jane L.
AU - Muraleedharan, Ranjithmenon
AU - Oatman, Nicole
AU - Klotter, Amanda
AU - Sengupta, Satarupa
AU - Waclaw, Ronald R.
AU - Wu, Jianqiang
AU - Drissi, Rachid
AU - Miles, Lili
AU - Raabe, Eric H.
AU - Weirauch, Matthew L.
AU - Fouladi, Maryam
AU - Chow, Lionel M.
AU - Hoffman, Lindsey
AU - Dewire, Mariko
AU - Dasgupta, Biplab
N1 - Publisher Copyright:
© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Background. Diffuse intrinsic pontine glioma (DIPG) is a high-grade brainstem glioma of children with dismal prognosis. There is no single unifying model about the cell of origin of DIPGs. Proliferating cells in the developing human and mouse pons, the site of DIPGs, express neural stem/progenitor cell (NPC) markers, including Sox2, nestin, vimentin, Olig2, and glial fibrillary acidic protein, in an overlapping and non-overlapping manner, suggesting progenitor cell heterogeneity in the pons. It is thought that during a restricted window of postnatal pons development, a differentiation block caused by genetic/epigenetic changes leads to unrestrained progenitor proliferation and DIPG development. Nearly 80% of DIPGs harbor a mutation in the H3F3A or the related HIST1H3B gene. Supporting the impaired differentiation model, NPCs derived from human induced pluripotent stem cells expressing the H3F3A mutation showed complete differentiation block. However, the mechanisms regulating an altered differentiation program in DIPG are unknown. Methods. We established syngeneic serum-dependent and independent primary DIPG lines, performed molecular characterization of DIPG lines in vitro and in an orthotopic xenograft model, and used small hairpin RNA to examine Olig2 function in DIPG. Results. The transcription factor Olig2 is highly expressed in 70%-80% of DIPGs. Here we report that Olig2 expression and DIPG differentiation are mutually exclusive events in vitro, and only DIPG cells that retained Olig2 in vitro formed robust Olig2-positive brainstem glioma with 100% penetrance in a xenograft model. Conclusion. Our results indicate Olig2 as an onco-requisite factor in DIPG and propose investigation of Olig2 target genes as novel candidates in DIPG therapy.
AB - Background. Diffuse intrinsic pontine glioma (DIPG) is a high-grade brainstem glioma of children with dismal prognosis. There is no single unifying model about the cell of origin of DIPGs. Proliferating cells in the developing human and mouse pons, the site of DIPGs, express neural stem/progenitor cell (NPC) markers, including Sox2, nestin, vimentin, Olig2, and glial fibrillary acidic protein, in an overlapping and non-overlapping manner, suggesting progenitor cell heterogeneity in the pons. It is thought that during a restricted window of postnatal pons development, a differentiation block caused by genetic/epigenetic changes leads to unrestrained progenitor proliferation and DIPG development. Nearly 80% of DIPGs harbor a mutation in the H3F3A or the related HIST1H3B gene. Supporting the impaired differentiation model, NPCs derived from human induced pluripotent stem cells expressing the H3F3A mutation showed complete differentiation block. However, the mechanisms regulating an altered differentiation program in DIPG are unknown. Methods. We established syngeneic serum-dependent and independent primary DIPG lines, performed molecular characterization of DIPG lines in vitro and in an orthotopic xenograft model, and used small hairpin RNA to examine Olig2 function in DIPG. Results. The transcription factor Olig2 is highly expressed in 70%-80% of DIPGs. Here we report that Olig2 expression and DIPG differentiation are mutually exclusive events in vitro, and only DIPG cells that retained Olig2 in vitro formed robust Olig2-positive brainstem glioma with 100% penetrance in a xenograft model. Conclusion. Our results indicate Olig2 as an onco-requisite factor in DIPG and propose investigation of Olig2 target genes as novel candidates in DIPG therapy.
KW - DIPG
KW - Olig2
KW - differentiation
UR - http://www.scopus.com/inward/record.url?scp=85026904770&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026904770&partnerID=8YFLogxK
U2 - 10.1093/neuonc/now299
DO - 10.1093/neuonc/now299
M3 - Article
C2 - 28339768
AN - SCOPUS:85026904770
SN - 1522-8517
VL - 19
SP - 1068
EP - 1078
JO - Neuro-oncology
JF - Neuro-oncology
IS - 8
ER -