# Targeting Oncogenic Regulation Through Unique DNA Structures in Lymphoma

> **NIH NIH P20** · ARKANSAS CHILDREN'S HOSPITAL RES INST · 2022 · $279,500

## Abstract

Summary
 Hijacking of the B-cell receptor (BCR) pathway drives chemoresistance in diffuse large B-cell lymphoma
(DLBCL). While inhibiting BCR-associated kinases (e.g., ibrutinib) has shown promise in other non-Hodgkin
lymphoma subtypes and leukemias, these therapies fail to achieve sustained responses in DLBCL patients. In
addition to acquired mutations in the targeted kinases, this disparity is related to the inherent resistance of DLBCL
from genetic lesions or up-regulation of non-kinase components that feed into the BCR pathway, such as scaffold
and adaptor proteins CARD11 and MYD88. Identifying new strategies to target this oncogenic signaling will
advance the knowledge of DLBCL pathobiology and the treatment of patients with this refractory-prone disease.
The overall goals of our research program are to provide insight into the deregulation of BCR signaling and
develop effective therapeutic approaches to inhibit key molecules in this lymphoma-specific pathway. We
recently discovered guanine (G)-rich elements upstream of the CARD11 and MYD88 transcription start sites
form G-quadruplex (G4) DNA secondary structures. Stabilization of these structures with small molecules
lowered mRNA levels suggesting a regulatory role in gene expression. Furthermore, chromatin
immunoprecipitation sequencing (ChIP-seq) revealed CARD11 and MYD88 G4 forming sequences aligned with
targeted loci of an enzyme called activation-induced cytidine deaminase (AID), which is implicated in mutation
of genes important in DLBCL. Based on this preliminary data, we hypothesize the promoter G4 structures
deregulate CARD11 and MYD88 expression via controlling transcription and facilitating mutations, and can serve
as targets to silence BCR oncogenic signaling. We will test our hypothesis in the following aims: (1) Identify the
mechanism by which the CARD11 and MYD88 promoter G4 structures regulate the BCR pathway, (2) Define
the involvement of G4 structures in the mechanism for AID induced CARD11 and MYD88 mutation, and (3)
Determine efficacy of silencing CARD11 and MYD88 transcription on tumor growth to develop lead molecules.

## Key facts

- **NIH application ID:** 10496403
- **Project number:** 2P20GM121293-06
- **Recipient organization:** ARKANSAS CHILDREN'S HOSPITAL RES INST
- **Principal Investigator:** Samantha Kendrick
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $279,500
- **Award type:** 2
- **Project period:** 2017-07-11 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496403

## Citation

> US National Institutes of Health, RePORTER application 10496403, Targeting Oncogenic Regulation Through Unique DNA Structures in Lymphoma (2P20GM121293-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10496403. Licensed CC0.

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