# Role of Methyltransferases in MYC-driven Medulloblastoma

> **NIH NIH P01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $348,719

## Abstract

Project Summary/Abstract
Medulloblastoma (MB) is a tumor of the hindbrain that occurs in children with a peak incidence between the ages
of 3 and 7. Based on extensive molecular evidence, medulloblastoma is classified into four major groups, among
which Group (G3) MB with MYC overexpression, carry the worse prognosis. Thus, novel therapies are needed
to effectively treat these aggressive brain tumors in children. Recent genome wide sequencing and 850K
methylation profiling showed that G3MB has a paucity of mutations, most of which occur in epigenetic regulatory
enzymes that modify histones. However, a significant proportion of MYC-driven G3 MBs do not harbor any
mutations suggesting that additional non-mutated epigenetic regulators, so called “hidden drivers”, might act as
oncogenes or tumor-suppressors, implicated in shaping the chromatin structure and driving G3 MB genesis. We
performed a dropout shRNA screen of 243 unique mouse epigenetic regulators, and the top hit was SMYD3, a
H4K5me1 methyltransferase that importantly regulates MYC expression. Systems biology reveals that SMYD3
is most overexpressed in G3 MBs that specifically overexpress MYC (type II) compared to the other G3 MB
subtypes and MB Groups. To address the role of SMYD3 in driving G3 MB, we will use multiple complementary
approaches in vitro and in vivo in both mouse and human G3MB to 1) assess how SMYD3 overexpression
contributes to G3MB tumorigenesis, 2) use mass spectrometry to identify interacting proteins and define the role
of SMYD3 in shaping the transcriptome, proteome and phosphoproteome, and 3) evaluate whether SMYD3 and
other epigenetic regulators could be considered as therapeutic targets for future clinical trials in MYC-driven
G3MB. Our ultimate goal is to identify epigenetic vulnerabilities that can be therapeutically targeted to treat the
most aggressive forms of the disease.

## Key facts

- **NIH application ID:** 10479007
- **Project number:** 5P01CA096832-17
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** MARTINE F. ROUSSEL (SHERR)
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $348,719
- **Award type:** 5
- **Project period:** 2003-04-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10479007

## Citation

> US National Institutes of Health, RePORTER application 10479007, Role of Methyltransferases in MYC-driven Medulloblastoma (5P01CA096832-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10479007. Licensed CC0.

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