# Mechanisms of Control of Lymphocyte Activation and Proliferation by a Critical Signaling Integrator

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $436,415

## Abstract

PROJECT SUMMARY/ABSTRACT
Antigen receptor signaling to NF-κB is a highly regulated, critical pathway for B and T lymphocyte activation
during the adaptive immune response. NF-κB controls many genes required for lymphocyte function including
genes that promote proliferation and survival. The inappropriate activation of NF-κB is associated with multiple
lymphomas, which frequently acquire mutations in signaling molecules that elicit their receptor-independent
constitutive NF-κB activity. CARD11 is a key scaffold protein that functions in both T cell receptor and B cell
receptor pathways to transmit signals from the engaged receptor to the activation of the IKK complex and NF-
κB. Aberrant CARD11-dependent signaling is required for the dysregulated proliferation of the activated B cell-
like (ABC) subtype of Diffuse Large B Cell Lymphoma (DLBCL), and mutations in CARD11, which
hyperactivate the protein, are found in ~10% of patient samples of ABC DLBCL. Previous work has established
that during normal signaling, CARD11 undergoes a transition from an inactive to an active signaling scaffold
that recruits several signaling cofactors into a complex that induces IKK activity. An Inhibitory Domain (ID) in
CARD11 controls this transition; it keeps CARD11 inactive in the basal state, but receives signals from the
engaged receptor that neutralize its inhibitory action and allow CARD11 to signal. Lymphoma-associated
mutations in CARD11 bypass normal activation and convert CARD11 into a constitutively active signaling
scaffold. However, it remains poorly understood how during normal antigen receptor signaling CARD11 is
converted to its active state, how precisely normal and oncogenic forms of CARD11 signal to the IKK complex
to activate NF-κB, and how DLBCL-associated gain-of-function CARD11 alleles achieve the transformation of
normal B cells into lymphoma. In this application we will 1) investigate how signaling potential and cooperating
mutations determine the extent of oncogenic CARD11-mediated aberrant B cell proliferation in vivo; 2)
investigate the role of a newly identified factor required for CARD11 activity in normal and oncogenic antigen
receptor signaling; and 3) dissect determinants required for several steps in the CARD11 signaling cycle. Our
studies will advance understanding of the mechanisms of antigen receptor signaling during lymphocyte
activation, illuminate how signaling proteins, especially scaffolds, achieve signal-induced activation during
normal physiological behavior, and improve our understanding of how the combination of genetic lesions found
in lymphoma determines disease severity. Our studies should reveal a previously unrecognized molecular
target for the development of new therapies designed to treat NF-κB-dependent cancers and other diseases
that result from aberrant immune cell behavior.

## Key facts

- **NIH application ID:** 10304147
- **Project number:** 5R01AI148143-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Joel L Pomerantz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $436,415
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304147

## Citation

> US National Institutes of Health, RePORTER application 10304147, Mechanisms of Control of Lymphocyte Activation and Proliferation by a Critical Signaling Integrator (5R01AI148143-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10304147. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*