# Targeting BRD4 in Chronic Lymphocytic Leukemia (CLL) Disease Progression to Richter's Transformation (RT)

> **NIH NIH R00** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Richter's transformation (RT) is an aggressive B-cell lymphoma that occurs in the setting of
chronic lymphocytic leukemia (CLL). RT is therapy-resistant and associated with short survival
and is the most common progression seen in patients receiving targeted therapies including the
BTK inhibitor ibrutinib. The molecular mechanisms driving RT are unknown, but if identified,
could yield discovery of potential therapeutic targets and predictive indicators for this incurable
disease. BRD4 is a bromodomain-containing protein that regulates transcription of genes critical
for cell growth and proliferation. Our preliminary results show BRD4 levels to increase during
CLL disease progression and its inhibition to down-modulate key genes relevant to CLL and RT
development. Moreover, our pilot studies revealed a unique BRD4-mediated immunomodulatory
signature wherein co-inhibitory immune checkpoint molecules were reduced following BRD4
inhibition in primary tumor cells. To date the biology of BRD4, implication of its inhibition and its
potential to correct immune defects has yet to be investigated in leukemia/lymphoma. We
hypothesize that dysregulation of BRD4 functions as a driver of RT representing a novel
therapeutic target for epigenetic intervention for this fatal disease. Two Specific Aims will
address this: In Aim we will determine the role of BRD4 in CLL-to-RT biology and identify a
novel gene signature underlying RT. In Aim 2 we will evaluate the anti-tumor and
immunomodulatory properties of BRD4 inhibition as a therapeutic epigenetic intervention
approach for aggressive CLL and RT. This study, if successful, will promote the development of
diagnostic and prognostic tests/markers predictive of CLL transformation to lymphoma and
introduce novel therapeutic approaches for this incurable disease.

## Key facts

- **NIH application ID:** 9938446
- **Project number:** 5R00CA208017-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Dalia ElGamal
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-07-11 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938446

## Citation

> US National Institutes of Health, RePORTER application 9938446, Targeting BRD4 in Chronic Lymphocytic Leukemia (CLL) Disease Progression to Richter's Transformation (RT) (5R00CA208017-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9938446. Licensed CC0.

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