# The Role of CARM1-Dependent Arginine Methylation of BRD4 in Hematopoiesis

> **NIH NIH F31** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $41,369

## Abstract

ABSTRACT:
 Acute myeloid leukemia (AML) is an aggressive and lethal disease characterized by the accumulation of immature
blood cells in the bone marrow. Epigenetic modifying proteins are emerging as important therapeutic targets in leukemia,
as they are one of the most commonly mutated class of genes in de novo AML and are targetable with small molecules.
Histone reader, bromodomain containing protein 4 (BRD4) and coactivator-associated arginine methyltransferase 1
(CARM1) have both been shown to have malignant functions in leukemia. Furthermore, perturbation of these proteins has
demonstrated a therapeutic potential for the treatment of AML. Recently, focused efforts have been made to develop
efficacious therapeutic drugs targeting these proteins and their associated pathways to treat AML. CARM1 inhibitors are
being investigated in preclinical development, while several BET inhibitors are currently being investigated in clinical
trials.
 Several studies have identified post translational modifications of BRD4 though the functional relevance of these
modifications is poorly studied. Our preliminary findings identify a novel CARM1-dependent asymmetric arginine
methylation of BRD4. Moreover, our data suggest a functional CARM1-BRD4 signaling axis in which CARM1
dimethylates BRD4, which results in the regulation of subcellular localization of BRD4 and its binding to the chromatin
promoting its oncogenic functions. We propose to study the role of CARM1 in regulating BRD4 function in AML cells and
to understand whether this post-translation modification of BRD4 is required for leukemia initiation and maintenance in
mouse models of the disease. From our preliminary data we hypothesize that the CARM1-mediated arginine methylation
of BRD4 increases its localization and binding to chromatin. Furthermore, perturbations of this methylation will result in
an eviction of chromatin-bound BRD4, in turn leading to improved survival through the suppression of the transcription of
oncogenic genes that drive AML pathogenesis.
 Though we have unearthed CARM1 as an efficacious target of AML and shown its beneficial effects on depleting
oncogenic signaling, the precise mechanisms in which CARM1 inhibition hinders AML development still remains a
question. By studying the substrates and interacting proteins of CARM1, such as BRD4, and defining its downstream
biological events, we will more fully understand the cellular machinery that drives AML and more efficiently devise
therapeutic strategies. We are confident that successful completion of our proposed study will provide experimental support
for the advancement of both BET and CARM1 inhibitors as a treatment for AML as well as inform the development of
novel AML targeted therapies.

## Key facts

- **NIH application ID:** 10068043
- **Project number:** 1F31CA254232-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Adnan Kasim Mookhtiar
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $41,369
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068043

## Citation

> US National Institutes of Health, RePORTER application 10068043, The Role of CARM1-Dependent Arginine Methylation of BRD4 in Hematopoiesis (1F31CA254232-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068043. Licensed CC0.

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