# DNMT3A in Development of Hematologic Malignancies

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $729,528

## Abstract

Abstract
DNA METHYLTRANSFERASE 3A (DNMT3A) has emerged over the past ~8 years as one of the
most important tumor suppressors in the hematopoietic system, being mutated across most types
of human hematologic malignancies, and found in greater than 20% of acute myeloid leukemias
(AMLs) as well as acute lymphoid leukemias (ALLs) and lymphomas. Through mechanisms that
are not understood, DNMT3A mutations are thought to provide a fertile ground for secondary
mutations which drive the frank malignancy. In the previous funding period, we sought to establish
and study a reliable tumor model of DNMT3A-associated malignancies using the recognized
collaboration between DNMT3A-mutation and the internal tandem duplication (ITD) of FLT3 which
results in highly penetrant malignancies of both myeloid and lymphoid types. Here, we will study
the very earliest events that represent the transition from clonal hematopoiesis to malignacy. We
hypothesize that DNMT3A mutations and NPM1 mutations collaborate effectively by enforcing
complementary epigenetic changes that serve to maintain mutated cells in an HSC-like state. We
expect that a key effect of this dysregulation is aberrant expression of HOX genes that drives self-
renewal. We will dissect the mechanisms through which this occurs here using mouse models,
human cell lines, and human primary samples. Our long-term goal is to use insights developed
here to enforce differentiation and develop new therapeutic strategies. We will (1) Identify the
epigenetic and molecular changes associated with the development of malignancies from
Dnmt3a-deficient hematopoietic progenitors. Using mice that have mutant alleles of Dnmt3a-KO
and inducible NPM1c, we will examine the concerted changes that occur at the epigenetic and
transcriptional levels in pre-malignant stem and progenitor cells. (2) Examine the dependencies
of AML with mutated DNMT3A, NPM1, and FLT3-ITD. We hypothesize this common sub-type of
AML is dependent on the sustained expression of particular genes such as Hox and Meis1. We
will examine this and other potential dependencies using CRISPR KO or targeted DNA
methylation. (3) Examine in human DNMT3A-mutated AML cells epigenome remodeling and
dependencies. We will validate targets identified in Aims 1 and 2, and explore the value of specific
modulators such as nuclear re- localization of NPM1, correction of the DNMT3A-mutant allele,
and re-methylation of specific target sites. These studies will reveal the stepwise epigenomic
changes that occur due to loss of DNMT3A that lead to AML as well as some of their
dependencies. This will lead to an improved understanding of how loss of DNMT3A promotes
malignancies, and potentially to new therapeutic strategies due to identification of new targets.

## Key facts

- **NIH application ID:** 9963149
- **Project number:** 5R01CA183252-07
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** MARGARET A. GOODELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $729,528
- **Award type:** 5
- **Project period:** 2014-09-11 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963149

## Citation

> US National Institutes of Health, RePORTER application 9963149, DNMT3A in Development of Hematologic Malignancies (5R01CA183252-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9963149. Licensed CC0.

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