# The role of epigenetic plasticity in acute myeloid leukemia cell persistence

> **NIH NIH R00** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $248,991

## Abstract

PROJECT SUMMARY
 Acute myeloid leukemia (AML) patients have poor outcomes, largely because current therapies fail to
eradicate all AML cells, leaving persistent cancer cells that drive relapse. The ability of AML cells to survive
therapy is associated with stem cell properties1,2. These primitive AML cells need to be eradicated to achieve
durable remissions. During my Ph.D. training with Dr. John Dick, I studied hematopoietic stem cells1,3 which
inspired me to specialize in epigenetic regulation of the stem cell state in AML. For my postdoctoral training, I
joined the laboratory of Dr. Bernstein, an expert in epigenetics, and developed an innovative technology to map
histone modifications in rare cells4. Using this technology, I describe with unprecedented precision how stem cell
genes are silenced by histone 3 lysine 27 trimethylation (H3K27me3), a repressive epigenetic modification that
is catalyzed by PRC2 and antagonized by KDM6. PRC2 is frequently impaired in AML, leading to enhanced
stem cell properties, but the role of the H3K27 demethylase KDM6 is unknown. I discovered that KDM6 promotes
AML cell fitness and is upregulated in AML cells with mutations in IDH1/2 (IDHmut), indicating a dependency of
IDHmut AML cells on KDM6 function. The objectives of this proposal are to (1) investigate the function of KDM6
using various human AML cell models, (2) evaluate KDM6 as a therapeutic target in IDHmut AML cells, and (3)
delineate the mechanism by which KDM6 promotes AML cell fitness by identifying its downstream targets. These
studies will uncover a novel epigenetic mechanism that drives AML and lay the foundation for the development
of KDM6 inhibitors to facilitate efficient eradication of AML cells, including those that persist through current
therapies.
 Dr. Bernstein is an outstanding mentor with a history of trainees that obtained group leader positions in
academia. He is an internationally respected leader in the fields of epigenomics, cancer and development with
appointments at the Massachusetts General Hospital (MGH), Harvard Medical School, American Cancer Society
and the Broad Institute. The research will be carried out at MGH, a prestigious research institute and medical
center that is part of a vibrant community that includes Harvard Medical School, Dana-Farber Cancer Institute,
Brigham and Women's Hospital and the Broad Institute, an environment that fosters collaborations and
intellectual exchange. A Research Advisory Committee of world-class physician-scientists will provide advice
and guidance: Drs. David Scadden, Jon Aster and Andrew Lane. Critical aspects of the research will be
completed through collaborations with Drs. Andrew Lane, David Weinstock and Charles Epstein.
 The K99/R00 award will provide me with the best opportunity to succeed in my career goals. The detailed
training plan includes a Research Advisory Committee and development of leadership and mentoring skills that
will be invaluable for a successful transition to ...

## Key facts

- **NIH application ID:** 9983630
- **Project number:** 5R00CA218832-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Peter van Galen
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,991
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983630

## Citation

> US National Institutes of Health, RePORTER application 9983630, The role of epigenetic plasticity in acute myeloid leukemia cell persistence (5R00CA218832-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983630. Licensed CC0.

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