# Targeting the Oncogenic Transcription Factor IRF4 in Hematological Malignancies

> **NIH NIH R15** · EAST TENNESSEE STATE UNIVERSITY · 2021 · $447,000

## Abstract

Project Summary
The oncoprotein interferon regulatory factor 4 (IRF4) is a lymphocyte-specific transcription factor that is
frequently overexpressed and mutated in hematological malignancies, including Epstein-Barr Virus (EBV)-
associated, AIDS-related lymphomas (ARLs), which are the leading cause of HIV/AIDS-related cancer deaths
even in the current antiretroviral therapy (ART) era. However, the precise mechanisms underlying IRF4-
mediated oncogenesis is poorly understood. We have shown that IRF4 is critical for survival of virus (EBV,
HTLV1)-transformed cells, and its depletion causes apoptosis, at least through transcriptional upregulation of the
oncogenic miRNA miR-155 and the adaptor protein LIMD1 that in turn participates in EBV Latent
Transmembrane Protein 1 (LMP1) signal transduction and is required for oxidative stress-induced autophagy,
amongst many other IRF4 transcriptional targets. We have also shown that IRF4 is activated through c-Src-
mediated tyrosine phosphorylation downstream of LMP1 signaling, in EBV-transformed cells, with the aid of
several unbiased “state-of-the-art” high throughput techniques including phosphotyrosine proteomics, and
ubiquitinomics. Furthermore, we have collected several lines of evidence in these studies showing that IRF4 is
ubiquitinated with K63-linked ubiquitin chains, and that apoptosis induces a smaller size of IRF4, which may be
a caspase-cleaved product and may represent a dominant negative mutant lacking the DNA-binding activity.
Correspondingly, a potential caspase-cleavage site proximal to C-terminus of its DNA-binding domain was
identified. Thus, the proposed study aims to test two hypotheses that:
and converts IRF4 to a dominant-negative pro-apoptotic mutant; and
1)
2)
 caspase-3 cleaves IRF4 in apoptosis
LMP1 signaling stimulates K63-linked
ubiquitination of IRF4 that promotes IRF4 transcriptional activity. These studies will provide novel mechanistic
insights into IRF4 posttranslational modifications in regulation of its activity and functions in virus-associated
hematological malignancies. Findings from these studies and future long-term pursuits will shed new light on the
importance of IRF4 in viral oncogenesis, and may identify the LMP1-IRF4 regulatory network as a potential
therapeutic target for treating EBV-associated, AIDS-related hematological malignancies.

## Key facts

- **NIH application ID:** 10113867
- **Project number:** 1R15DE029621-01A1
- **Recipient organization:** EAST TENNESSEE STATE UNIVERSITY
- **Principal Investigator:** Shunbin Ning
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $447,000
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113867

## Citation

> US National Institutes of Health, RePORTER application 10113867, Targeting the Oncogenic Transcription Factor IRF4 in Hematological Malignancies (1R15DE029621-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113867. Licensed CC0.

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