DIPG-59. UPREGULATION OF PRENATAL PONTINE ID1 SIGNALING IN DIPG. (4th December 2020)

• Record Type: Journal Article
• Authors: Harris, Micah K; Yadav, Viveka Nand; Stallard, Stefanie; Woo, Rinette; Siddaway, Robert; Qin, Tingting; Mullan, Brendan; Miklja, Zachary; Siada, Ruby; Ravindran, Ramya; Cao, Xuhong; Pasternak, Amy; Castro, Maria G; Lowenstein, Pedro R; Mody, Rajen; Chinnaiyan, Arul; Hawkins, Cynthia; Desprez, Pierre; McAllister, Sean; Venneti, Sriram; Koschmann, Carl
• Is Part Of: Neuro-oncology. Volume 22(2020)Supplement 3
• Page Start: iii298
• Page End: iii299
• Publication Date: 2020-12-04
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa222.104
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with no curative therapies. Inhibitor of DNA binding (ID) proteins are key regulators of gene differentiation during embryogenesis. Previous work has shown that H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes, but this has not been validated in human DIPG, nor has the regulation and targetability of ID1 been explored in DIPG. RESULTS: Analysis of post-mortem tissue and multiple human datasets showed ID1 to be elevated in DIPG, and to correlate with reduced survival. In a multi-focal autopsy of a DIPG case, we also found ID1 expression to be heterogeneous and to correlate with tumor invasion. Chromatin immunoprecipitation qPCR (ChIP-qPCR) revealed elevated H3K27ac and low H3K27me3 at ID1 regulatory regions (enhancers/promoters) in DIPG tissue compared to normal brain, regardless of H3 or ACVR1 mutation status. Analysis of publicly-available ISH and ChIP-sequencing data of developing murine brains revealed H3K27ac at ID1 enhancers to be elevated in the prenatal hindbrain compared to prenatal forebrain and midbrain, and all postnatal brain regions. ID1 shRNA-mediated knockdown of primary human H3K27M DIPG cells (DIPG007) significantly reduced invasion and migration. We also treated DIPG007 cells with cannabidiol (CBD) and found reduced viability at clinically relevant dosing (IC50=2.4 uM) with dose-dependent reduction in ID1 protein. CONCLUSIONS: These findings indicate that a multifactorial (genetic and regionally-based) epigenetic upregulation of ID1 drives DIPG invasiveness and is targetable with CBD. ID1 knockdown and CBD treatment experiments in murine models of DIPG are ongoing.