# Determining the Role of DNA Methylation Deregulation in Oncogenesis

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $348,584

## Abstract

PROJECT SUMMARY/ABSTRACT
Somatic mutation of DNA (cytosine-5)-methyltransferase 3A (DNMT3AMut) occurs in >20-30% of
acute myeloid
 (AML) patients making it one of the most frequently mutated genes in this deadly human disease.
DNMT3AMut correlates with poor clinical outcome of AML. However, the molecular mechanism by which
DNMT3AMut contributes to AML development remains far from clear. We reported that DNMT3AMut promotes
cell transformation and establishes a bona fide AML phenotype in mice possessing the initiating RAS mutation.
Integrated transcriptome and epigenomic profiling of this new murine AML model revealed that DNMT3AMut
binds directly to enhancers of target genes inducing focal DNA hypo-methylation at binding sites. These
DNMT3AMut-mediated events result in aberrant activation of a gene-expression program controlling stem cell
self-renewal (notably a Meis1 node), anti-differentiation and tumor cell pro-survival. Our discovery-based
epigenetic inhibitor screen further identified the DOT1L histone methyltransferase to be essential for
DNMT3AMut-induced aberrant gene activation. We hypothesize that DNMT3AMut induces focal DNA hypo-
leukemia
methylation at gene enhancers promoting DOT1L-dependent activation of self-renewal (notably Meis1), anti-
differentiation and tumor pro-survival genes, which collectively contribute to AML pathogenesis.
Dissecting the
molecular events and mechanism underlying
DNMT3AMut
-mediated AML progression should provide critical
insights into new treatment strategies. Towards this goal, we will use cutting-edge CRISPR/Cas9 technologies
to define the causal role for enhancer DNA hypomethylation due to DNMT3AMut in inducing aberrant gene
activation and promoting AML determine what DNMT3AMut-activated gene pathways are
essential for AML development in mice in vitro and in vivo
(aim 1); we will
through loss-of-function studies in our established
murine AML models (aim 2); and third, in a translational aim, we will use human AML cell lines and primary
patient-derived xenograft (PDX) models bearing DNMT3AMut to define effects of DNMT3AMut on epigenomic
alteration, gene expression deregulation and malignant growth in human AML (aim 3). We expect to define the
DNMT3AMut-induced epigenetic/gene changes in AML and expect to identify the pathway by which DNMT3AMut
promotes AML progression. Because certain identified pathways such as DOT1L and Bcl2 are potentially
druggable with the existing compounds
, completion of our proposed research should not only promote a new
mechanistic understanding of
DNMT3AMut-associated
AML but will also yield innovative therapeutics for the
treatment of affected cancer patients.

## Key facts

- **NIH application ID:** 9880405
- **Project number:** 5R01CA215284-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** G Greg Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,584
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880405

## Citation

> US National Institutes of Health, RePORTER application 9880405, Determining the Role of DNA Methylation Deregulation in Oncogenesis (5R01CA215284-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9880405. Licensed CC0.

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