# Role of the Histone Methyltransferase MLL4 in Medulloblastoma

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $366,341

## Abstract

PROJECT SUMMARY
 Medulloblastoma (MB) is the most common malignant primary brain tumor of children. MB development often
results from the dysregulation of cellular signaling pathways, such as sonic hedgehog and wingless. Recently,
epigenetic aberrations, which represent heritable aberrations in gene expression or cellular phenotypes without
changes in DNA sequences, have emerged as a major driving force for tumorigenic events. Histone lysine
methylation, a type of histone modification, is a hallmark of epigenetic and transcriptional regulation of gene
expression and is modulated by histone methylation modifiers. In contrast to great advances in our understanding
of cellular signaling pathways in MB genesis, the pathogenic role of altered histone methylation modifiers in MB
development remains largely unknown. Of histone methylations, methylated histone H3 lysine 4 (H3K4) occupies
most human gene promoters and is associated with active or poised genes. We previously showed that the H3K4
methyltransferase mixed-lineage leukemia 4 (MLL4; also called MLL2, ALR, and KMT2D) is indispensable for
retinoic acid (RA)-induced neuronal differentiation of the model human stem cell line NT2/D1. Consistent with
this, we also demonstrated that MLL4 activates the expression of several differentiation-specific genes by
depositing methylated H3K4. Our additional results showed that Mll4 brain-specific knockout (BSKO) mice
developed spontaneous MBs. These findings are consistent with recent massive sequencing studies of human
MBs showing that the MLL4 gene often undergoes somatic mutations and deletions. Our long-term goal is to
define the tumor-suppressive role of MLL4 in medulloblastoma pathogenesis. Our analysis of expression data
suggests that Mll4-loss-induced MBs are close to the most malignant and metastatic MB subtype Group 3. Based
on these definitive findings, our central hypothesis is that MLL4 acts as a tumor-suppressor against MB by
activating the expression of tumor suppressor genes via regulation of epigenetic signatures. Here, we propose
to study to 1) Assess the role of MLL4 in MB development using genetically engineered mouse models; 2)
Determine the molecular mechanism underlying the genesis of Mll4-loss-driven MB; 3) Characterize the effect of
Mll4 loss on epigenetic signatures during MB genesis. These studies will reveal the previously unknown
epigenetic mechanism underlying MB pathogenesis and provide beneficial information for the development of
MB therapies.

## Key facts

- **NIH application ID:** 9938460
- **Project number:** 5R01CA207109-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Min Gyu Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,341
- **Award type:** 5
- **Project period:** 2017-06-07 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938460

## Citation

> US National Institutes of Health, RePORTER application 9938460, Role of the Histone Methyltransferase MLL4 in Medulloblastoma (5R01CA207109-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9938460. Licensed CC0.

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