# Regional selectivity of oncohistone H3K27M on glial development and glioma pathogenesis

> **NIH NIH F31** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC · 2021 · $42,036

## Abstract

Abstract:
Diffuse intrinsic pontine glioma (DIPG) is an incurable high-grade glioma arising in the brainstem primarily in
younger children. DIPG 2-year survival rate is <10% due to its unresectable tumor location and resistance to
radiation and available therapeutics. This emphasizes the need for better understanding of the underlying
pathogenesis of DIPG to identify new therapeutic vulnerabilities. Histone H3 Lys27Met (K27M) mutations are a
unifying molecular feature observed ~80% of DIPGs and pediatric diffuse midline gliomas (DMG). The high
frequency of K27M and their exclusivity to childhood DIPG and DMG suggests K27M has a unique selective
advantage in a distinct spatiotemporal setting for tumorigenesis. Understanding the regional selectively of K27M
and its phenotypic and molecular effects will further elucidate oncogenic mechanisms and help identify new and
better treatment options. The Baker laboratory developed a genetically engineered mouse model harboring a
conditional knock-in of K27M into the endogenous H3f3a locus which allows the mutation to be studied in a
physiologically and developmentally relevant manner. With this model, we showed K27M cooperates with Pdgfra
activation and or p53 loss to drive spontaneous gliomagenesis selectively in brainstem and hindbrain locations.
K27M causes dramatic loss of the repressive H3K27me3 but only specific changes in gene expression related
to neurodevelopment. Single-cell RNA-seq of human K27M DIPGs reveals oligodendrocyte precursors (OPC)
are the main proliferative and stem-like population present in DIPGs. We have also showed that depletion of
K27M in patient-derived xenografts induces oligodendrocyte (OL) differentiation signatures, decreases stemness
signatures, and reduces proliferation and tumor growth. In total, these studies indicate a role for K27M in regional
selectivity of brainstem tumorigenesis along with altered OL differentiation, promoting OPC-like state. However,
many questions still remain regarding K27M and DIPG. Why is K27M found almost exclusively in brainstem and
midline pediatric glioma? What are the oncogenic effects and mechanisms of K27M alone? I will utilize our K27M
knock-in mice to dissect the regional effects of H3 K27M on glial development and tumorigenesis in vivo (Aim 1)
and evaluate the regional K27M-mediated epigenetic and transcriptomic dysregulation in oligodendrocyte
development to identify K27M DIPG dependencies (Aim 2). Through completion of these studies, we will gain
insights into the molecular mechanisms and spatiotemporal context of K27M that disrupt development and
promote tumorigenesis which will help to direct therapeutic development to target the molecular programs
involved that are specific to region and cellular state.

## Key facts

- **NIH application ID:** 10315763
- **Project number:** 1F31CA265285-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
- **Principal Investigator:** Kaitlin Budd
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $42,036
- **Award type:** 1
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315763

## Citation

> US National Institutes of Health, RePORTER application 10315763, Regional selectivity of oncohistone H3K27M on glial development and glioma pathogenesis (1F31CA265285-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10315763. Licensed CC0.

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