# Functional characterization and rational therapeutic targeting of 18q DNA copy number gains in diffuse large B-cell lymphoma

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $418,885

## Abstract

Project Summary
Diffuse large B-cell lymphoma (DLBCL) is the most common form lymphoma and is conventionally
treated with a combination of chemotherapeutics with the anti-CD20 antibody, Rituximab. Although more
than half of patients can be cured with this approach, the remainder have a dire prognosis with a short
survival. Despite the variability in patient outcome, there are currently no routinely utilized molecular
biomarkers that can be employed for risk stratification or to direct a specific therapy. That is, precision
medicine does not currently exist for DLBCL.
We have identified a genetic alteration on the q-arm of chromosome 18 (18q) that is associated with an
aggressive subtype of DLBCL, and defined the TCF4 and BCL2 genes as critical targets at this locus.
The BCL2 gene encodes an important oncogene that prevents cell death, and can be targeted with the
inhibitor Venetoclax. The TCF4 gene encodes a transcription factor protein that we have found to drive
key malignant properties of lymphoma, such as promoting the expression of the MYC oncogene and the
B-cell receptor. In addition, we have defined a way to eliminate TCF4 expression using a novel type of
protein-degrader molecules that are directed towards BET proteins. This therefore provides an exciting
rational therapeutic avenue for targeting TCF4. We hypothesize that combining this with an inhibitor of
BCL2 will target both genes that are activated by 18q alterations, and provide a precision medicine
approach for treating this aggressive subset of DLBCL.
Here, we are proposing to investigate the function of 18q alterations in DLBCL and validate the
mechanism by which we believe this genetic event leads to lymphoma. We will also perform pre-clinical
investigation of combinations of BET and BCL2 inhibitors for the specific therapeutic targeting of 18q
alterations. Together, this work will advance our understanding of DLBCL disease biology and may lead
to advances in precision medicine for this disease.

## Key facts

- **NIH application ID:** 10746128
- **Project number:** 5R01CA240839-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Michael Richard Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,885
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746128

## Citation

> US National Institutes of Health, RePORTER application 10746128, Functional characterization and rational therapeutic targeting of 18q DNA copy number gains in diffuse large B-cell lymphoma (5R01CA240839-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10746128. Licensed CC0.

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