# Characterization of a novel suppressor of oncogenic CARD11 signaling.

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2021 · $46,036

## Abstract

Project Summary/Abstract
 Non-Hodgkin lymphomas are a major cause of death in the United States, yet the molecular causes are
not thoroughly understood. In many lymphomas including Diffuse Large B Cell Lymphoma (DLBCL), the scaffold
protein CARD11 is mutated, and this can drive aberrant activation of the transcription factor NF-κB, as well as
JNK and mTOR. In healthy lymphocytes, CARD11 connects antigen receptor engagement to NF-κB, JNK, and
mTOR activation, but in lymphoma, this signaling can become dysregulated and lead to aberrant lymphocyte
proliferation, activation, and survival. Downregulation of CARD11 signaling can therefore be useful in treating
lymphoma, but there is currently not a complete mechanistic understanding of signal transduction through
CARD11 in healthy and diseased lymphocytes. Recent mass spectrometry screens have identified QRICH1 as
a novel negative regulator of CARD11 signaling to NF-κB. QRICH1 is a highly conserved protein without a known
function. Mutations in QRICH1 have been identified in individuals with developmental delay disorders and
chondrodysplasia, but QRICH1 has not been thoroughly studied on the molecular level. Some DLBCL cases
have QRICH1 copy number losses, but QRICH1 has never before been implicated in immune signaling or linked
to CARD11. In preliminary studies, QRICH1 physically interacts with CARD11 and can inhibit NF-κB activation
by wild-type and oncogenic CARD11. The proposed work aims to 1) determine the mechanism by which QRICH1
regulates CARD11 signaling, and 2) characterize the role of QRICH1 in B cell proliferation and survival. In order
to elucidate the mechanism of CARD11 inhibition by QRICH1, a deletion analysis will be performed to determine
the region(s) of QRICH1 that are necessary and/or sufficient for inhibition, and the interactions between QRICH1,
CARD11, and known CARD11 cofactors will be characterized. The signaling step(s) that QRICH1 acts on will
be determined by comparing CARD11 signaling events in wild-type and QRICH1-deficient Jurkat T cells. The
effect of QRICH1 on CARD11 signaling to JNK and mTOR will be resolved by comparing JNK and mTOR
activation markers in wild-type and QRICH1-deficient Jurkat T cells. To characterize the role of QRICH1 in B cell
proliferation and survival, QRICH1 will be knocked out in DLBCL-derived cell lines, and the effect on
growth/proliferation will be quantified using a flow-cytometry based assay. QRICH1 knockout primary B cells with
and without a CARD11 gain-of-function mutation will then be injected into Rag1-/- mice, and injected B cell
proliferation and survival will be quantified by flow-cytometry. Finally, a QRICH1fl/fl mouse has been generated
and will be crossed to Mb1-Cre for conditional knockout of QRICH1 in B cells. B cell expansion and activation
will be quantified by flow-cytometry, and QRICH1fl/fl Mb1-Cre mice with and without a CARD11 GOF mutation
will be monitored for B cell lymphoma. This work will advance knowledge of CARD11 si...

## Key facts

- **NIH application ID:** 10212285
- **Project number:** 5F31CA254167-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Nicole Marie Carter
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212285

## Citation

> US National Institutes of Health, RePORTER application 10212285, Characterization of a novel suppressor of oncogenic CARD11 signaling. (5F31CA254167-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10212285. Licensed CC0.

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