# The role of H3K79 methylation in IDH-mutant leukemia

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $436,506

## Abstract

Project Summary
Mutant forms of isocitrate dehydrogenase (IDH) have been identified in 20% of AML. The goal of
this project is to better understand the effects of mutant IDH on chromatin, and to develop
novel therapies for IDH-mutant AML. Mutant forms of IDH1/2 gain a neomorphic function,
producing 2-hydroxyglutarate (2HG) instead of the normal metabolite αKG. 2HG inhibition of
TET2, which mediates DNA hydroxymethylation, is a major mechanism of transformation by
mutant IDH. However, 2HG also inhibits JmjC domain containing histone demethylases. Whether
inhibition of JmjC demethylases and altered histone methylation contributes to
leukemogenesis is currently not known. This project investigates the role of histone 3 lysine 79
methylation (H3K79me) in mutant-IDH mediated leukemogenesis. H3K79 methylation is
increased in response to expression of mutant IDH, or exogenous exposure to 2HG, suggesting
the existence of an H3K79 demethylase that is inhibited by 2HG. H3K79 is methylated by DOT1L.
A contribution of aberrant H3K79 methylation to IDH–mutant leukemogenesis is highly relevant as
a pharmacologic inhibitor of DOT1L is currently in clinical trials. This project will investigate
whether DOT1L is required in IDH-mediated leukemogenesis using a murine leukemia model
(SA1) as well as detailed analysis of changes in chromatin and gene expression in patient
samples (SA2). Finally, the project aims to identify a demethylase for H3K79 (SA3).

## Key facts

- **NIH application ID:** 9918256
- **Project number:** 5R01CA201230-06
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** KATHRIN M BERNT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,506
- **Award type:** 5
- **Project period:** 2017-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918256

## Citation

> US National Institutes of Health, RePORTER application 9918256, The role of H3K79 methylation in IDH-mutant leukemia (5R01CA201230-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9918256. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*