# Role of the K27M histone mutation in midline gliomas initiated in oligodendrocyte progenitors

> **NIH NIH R21** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $229,500

## Abstract

Project Summary
Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), is a rare form of pediatric tumor
that arises in the brainstem of children, and is the leading cause of death among children with a brain tumor. The
current standard of care is radiotherapy, which only modestly improves survival. The lack of clinically relevant
models is a major barrier to developing effective therapies for children with DMG. A novel heterozygous
Lys27Met (K27M) mutation has been shown to occur in histones H3.3/3.1 in ~80% of DIPGs. However, the
mechanisms by which the histone mutations promote brainstem gliomagenesis have not been fully elucidated.
Several lines of evidence implicate Olig2-expressing (oligodendrocyte) progenitor cells (OPCs) in the brainstem
as the likely cell-of-origin for DIPG, especially for the subtype bearing the H3.3K27M mutation. Because
downstream consequences of oncogenic mutations are dependent on the tumor cell-of-origin, it is critical to
develop and characterize a mouse model of midline gliomas initiated in OPCs to accelerate DIPG research and
therapeutic development. Here, we propose to investigate the role of the H3.3K27M mutation in a novel DIPG
mouse model where midline tumors are initiated in OPCs. Specifically, we will perform thorough tumor biologic
and molecular characterization of brainstem tumors originating from OPCs, and perform a comparative analysis
of Nestin cell-of-origin tumors. We hypothesize that the phenotypic and molecular effects of H3.3K27M in OPC-
initiated tumors will be distinct from Nestin-initiated tumors, thus identifying novel therapeutically actionable
endpoints of the histone mutation. Thus, our study will credential the first immunocompetent mouse model of
DIPG initiated in OPCs, providing a novel platform to the DIPG research community to perform mechanistic and
translational research. Elucidation of the downstream consequences of the histone mutation in OPCs, along with
improved understanding of its cell-of-origin based effects, will help lay the foundation for future preclinical and
clinical studies of DIPG and other midline gliomas based on the molecular underpinnings of the disease.

## Key facts

- **NIH application ID:** 9873499
- **Project number:** 1R21NS114431-01
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Oren Josh Becher
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $229,500
- **Award type:** 1
- **Project period:** 2019-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873499

## Citation

> US National Institutes of Health, RePORTER application 9873499, Role of the K27M histone mutation in midline gliomas initiated in oligodendrocyte progenitors (1R21NS114431-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9873499. Licensed CC0.

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