# Mutations in Topoisomerase IIbeta result in B cell immunodeficiency

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $395,000

## Abstract

Project Summary/Abstract
The study of rare immunodeficiency patients has been extremely instructive to our understanding of B cell
development and human disease, revealing mechanisms of B cell development, central tolerance and
protection from infection. Syndromic immunodeficiencies, in which the physical malformations are often
more pronounced than the underlying immunologic defects, are less frequently studied and less well
understood. We recently discovered that mutations in TOP2B underlie the autosomal dominant syndromic B
cell immunodeficiency (Hoffman syndrome). Topoisomerases are essential genes required for relaxation of
topological stress during DNA replication and gene transcription, acting to prevent the generation of free
DNA breaks. We recently reported the first description of a role for TOP2B in a monogenetic human disease,
and revealed that heterozygous, dominant negative mutations in the DNA-binding domain of TOP2B led to
negative effects on development and function of B cells, while T cell activation was not affected. In this New
Investigator proposal, we take a bold, multi-species approach using novel S. cerevisiae models, innovative
genetically engineered mice developed by our group, the largest collection of TOP2B mutations in patients
with TOP2b mediated immunodeficiency, as well as newly developed patient- derived induced pluripotent
stem cells (iPSCs) to explore our hypotheses in an otherwise unobtainable human system. The central
hypothesis is that loss of enzymatic function leads to erroneous gene transcription, limited V(D)J
recombination, and subsequently the failure of normal B cell differentiation and function. Three specific aims
are proposed to test this hypothesis. Specific Aim 1 will determine how mutations in TOP2B generate B cell
immunodeficiency through malfunction in the ability to create and re- seal double strand breaks. In vitro and
in vivo experiments will examine how patient-associated mutations in TOP2B lead to impaired homologous
recombination and non-homologous end joining, disrupting early B cell development. Studies of genomic
interactions will examine how mutant Top2b impacts chromatin loop extrusion and impairs fundamental
mechanisms of V(D)J recombination and class switching. Specific Aim 2 will determine how mutations in
TOP2B impact the recruitment of repair proteins to sites of double strand breaks, leading to reduced break
repair, and resulting in reduced efficacy of nonhomologous end joining.
Finally, Specific Aim 3 will delineate how Top2b enzymatic function modulates B cell development. Using our
distinctive murine models including knock-in and conditional murine models, and iPSCs, we have a unique
opportunity to understand the molecular mechanisms underlying this B cell immunodeficiency.

## Key facts

- **NIH application ID:** 10786524
- **Project number:** 1R56AI175127-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Lori Broderick
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $395,000
- **Award type:** 1
- **Project period:** 2023-03-17 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786524

## Citation

> US National Institutes of Health, RePORTER application 10786524, Mutations in Topoisomerase IIbeta result in B cell immunodeficiency (1R56AI175127-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10786524. Licensed CC0.

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