# Targeting EGR1 signaling pathways in diffuse large B cell lymphoma

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $349,612

## Abstract

ABSTRACT
Diffuse large B cell lymphoma (DLBCL), which represents 30% to 40% of newly diagnosed lymphomas,
comprises two main molecular subtypes: activated B cell-like (ABC) and germinal center B cell-like (GCB). ABC
DLBCL is more aggressive and less curable. More than 50% of patients with ABC DLBCL are refractory to or
relapse from current frontline immunochemotherapy. Clinical use of ibrutinib, a selective inhibitor for Bruton
tyrosine kinase (BTK) in the B cell receptor (BCR) signaling pathway, has achieved an initial response rate of
30%-40% in refractory/relapsed ABC DLBCL. Primary and acquired drug resistance, however, are still significant
and impact the long-term survival of more than 60% of these patients. Therefore, understanding and targeting
ibrutinib resistance mechanisms is an unmet clinical need. The BCR and JAK1/STAT3 signaling pathways are
essential for the survival and proliferation of ABC DLBCL cells. We discovered that EGR1 is a converged
downstream target of both pathways in ABC DLBCL and the level of EGR1 expression is elevated in ABC DLBCL
compared with normal human tonsils and lymph nodes. We revealed novel mechanisms of EGR1 in
transcriptional activation and repression of target genes with strong translational impact in treating aggressive
lymphoma. EGR1 mediates transcriptional activation through the p300/H3K27ac/BRD4 axis to induce MYC
expression and activate MYC target genes. Synergistic inhibition of cell growth was observed between EGR1
shRNA and AZD5153, a novel BRD4 inhibitor that is currently under clinical investigation. On the other hand,
EGR1 mediates transcriptional repression of the type I interferon pathway genes, expression of which otherwise
causes cancer cell death. Consistently, EGR1 knockdown by shRNA synergizes with the type I interferon inducer
lenalidomide in growth inhibition of ABC DLBCL cells in vitro and in a xenograft mouse model. Using newly
derived, ibrutinib-resistant ABC DLBCL cell lines, we demonstrated that EGR1 is among the most highly
expressed genes relative to ibrutinib-sensitive parental cells, and co-targeting of BRD4 and interferon signaling
inhibits growth of ibrutinib-resistant cells in vitro and in vivo. Based on these discoveries, the central hypothesis
is that EGR1 is a unique oncogenic driver orchestrating multiple important signaling pathways and represents
therapeutic vulnerability in patients with ABC DLBCL, especially for those with ibrutinib resistance. To test our
hypothesis, we will pursue the following specific aims: (1) Elucidate effects of EGR1 on oncogenesis; (2)
Establish the role of EGR1 in ibrutinib resistance; and (3) Co-target EGR1 downstream BRD4 and type I
interferon signaling to overcome drug resistance in DLBCL. Dissecting the transcriptional activation and
repression modules of EGR1 in DLBCL tumorigenesis and ibrutinib resistance is essential because the novel
mechanistic insights will provide a molecular basis for developing the most effective therapeutic ...

## Key facts

- **NIH application ID:** 10340232
- **Project number:** 1R01CA266354-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Lixin Rui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,612
- **Award type:** 1
- **Project period:** 2021-12-20 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10340232

## Citation

> US National Institutes of Health, RePORTER application 10340232, Targeting EGR1 signaling pathways in diffuse large B cell lymphoma (1R01CA266354-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10340232. Licensed CC0.

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