# Enhancer RNA-mediated Tumor Suppressor Gene Expression in Normal and Malignant Hematopoiesis

> **NIH NIH K01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $40,610

## Abstract

PROJECT SUMMARY/ABSTRACT
The candidate has recently been expanding his strong expertise in molecular biology of solid cancer to
embrace important skills and concepts in RNA biology, hematopoiesis and leukemia, and to transition to an
independent researcher. His long-term goals are to understand how lineage-control transcription factors having
tumor suppressor functions are regulated in normal and malignant hematopoiesis and to exploit this
understanding in modulating their expression for preventative and therapeutic purposes. The objective of his
KO1 proposal is to determine how PU.1, a critical master hematopoietic transcription factor is regulated in
normal and malignant hematopoiesis. PU.1 is also a key tumor suppressor in acute myeloid leukemia (AML).
PU.1 expression in myeloid cells is induced by the interaction between the distal enhancer termed the
upstream regulatory element (URE), and the proximal promoter region (PrPr). Reduction in PU.1 expression
levels due to URE deletion has severe impacts on myeloid cell development leading to AML development. It
remains unclear what regulates URE-PrPr long-range interaction. In this study, the candidate will determine the
role and mechanism by which an enhancer RNA regulates PU.1 expression in normal and malignant
hematopoiesis. The following specific aims will be pursued: (1) to identify that the enhancer RNA induces PU.1
expression and is important for normal hematopoiesis, (2) to define the mechanism by which it induces PU.1
expression at the chromatin level, and (3) to establish that it inhibits AML progression by restoring proper
chromatin structure at the PU.1 locus thereby leading to PU.1 reactivation. Completion of these aims will
provide new insights into the nuclear functions of noncoding RNAs in normal and malignant hematopoiesis,
and provide a scientific basis for reactivating tumor suppressor genes by restoring proper chromatin structure.
Ultimately, this could be expected to result in the development of novel molecular therapeutic approaches for
AML. These aims will be achieved by using a variety of approaches including RNA interactions and gene
regulation via chromatin structure with the use of transgenic, knockout and engraftment mouse models. During
the award period, the candidate will focus on attaining new skills related to these proposed approaches,
building his expertise and conceptual knowledge regarding gene regulation by ncRNAs in hematopoiesis and
leukemia, and obtaining independent RO1-type grant. The candidate has assembled a strong mentor team.
His primary mentor, Dr. Daniel Tenen, is a well-known expert in gene regulation of hematopoiesis and
leukemia. In addition, the external advisor committee will monitor his research and career development
progress. Furthermore, he has unparalleled access to resources and expertise at the Beth Israel Deaconess
Medical Center and neighboring Harvard-affiliated institutions. Therefore, the candidate has the expertise,
motivation, men...

## Key facts

- **NIH application ID:** 10246466
- **Project number:** 5K01CA222707-05
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Bon Q Trinh
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,610
- **Award type:** 5
- **Project period:** 2017-09-20 → 2022-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246466

## Citation

> US National Institutes of Health, RePORTER application 10246466, Enhancer RNA-mediated Tumor Suppressor Gene Expression in Normal and Malignant Hematopoiesis (5K01CA222707-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246466. Licensed CC0.

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