# Overcoming Drug Resistance Driven by BCL10 Mutations in Diffuse Large B Cell Lymphoma

> **NIH NIH F30** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $51,036

## Abstract

Project Summary
 Diffuse large B cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma and the most common
hematologic malignancy. DLBCL exhibits significant molecular and clinical heterogeneity, yet all patients are
treated with standard chemoimmunotherapy. As such, there is a strong clinical need to identify biomarkers of
drug response and novel therapies to improve patient outcomes. BCL10 mutations are prevalent among DLBCL
subtypes and recurrent mutations frequently truncate the BCL10 protein’s regulatory C-terminus. BCL10 is a
core component of the CARD11 (CARMA1)-BCL10-MALT1 complex, which activates downstream oncogenic
pathways like JNK and NF-kB in DLBCL; however, the mechanisms by which BCL10 mutations promote
lymphomagenesis in DLBCL are poorly understood. Recent results implicate BCL10 mutations in the induction
of NF-kB signaling and MALT1 protease activity and Bruton’s Tyrosine Kinase inhibitor (BTKi) resistance. The
overall objective is to understand the role of BCL10 mutations in DLBCL, to determine mechanisms of drug
resistance and to identify alternative treatment strategies for patients with these mutations. The central
hypothesis that BCL10 mutations are activating in nature, driving lymphomagenesis and resistance to BTKis,
will be tested through the following specific aims: 1) Understand the role of BCL10 mutations in
lymphomagenesis using genetically accurate in vivo models, and 2) Identify alternative therapeutic
targets to overcome drug resistance mediated by BCL10 mutations. Aim 1 will characterize survival and
tumor incidence of a novel murine model generated in the lab containing an inducible BCL10 truncation mutation
expressed on the ROSA26 locus of C57BL/6J mice. The model mimics human disease through B-cell-specific
activation of BCL10 mutations using Cre-recombination and will also be crossed with mice overexpressing BCL6,
which occurs in context with BCL10 mutations. Aim 2 will identify compounds to attack BCL10 mutated cells
alone or in combination with BTKis by implementing small molecule synergy screens that target the BCR, NF-
kB and parallel signaling pathways. The expected outcome is the creation of genetically accurate in vivo models
of BCL10 mutations to understand their lymphomagenic potential, to define BCL10 as a biomarker of BTKi
resistance, and to identify novel, targetable dependencies induced by BCL10 mutations. The proposed research
is significant because it will uncover mechanisms of lymphomagenesis, identify biomarkers to guide clinical
decision-making in DLBCL and discover potential drug targets to overcome resistance or synergize with existing
therapies. Also, these studies are innovative because the described mouse model will be the first to characterize
BCL10 mutations in vivo and will provide a novel context to study lymphomagenesis and drug resistance driven
by BCL10 mutations. Overall, this research will have positive impacts as identifying BCL10 as a biomarker for
response to therapy ...

## Key facts

- **NIH application ID:** 10314594
- **Project number:** 1F30CA265106-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Caroline Alice Coughlin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314594

## Citation

> US National Institutes of Health, RePORTER application 10314594, Overcoming Drug Resistance Driven by BCL10 Mutations in Diffuse Large B Cell Lymphoma (1F30CA265106-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10314594. Licensed CC0.

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