# Role of CXCR4 in immunoglobulin light chain recombination

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $579,598

## Abstract

PROJECT SUMMARY
In B lymphopoiesis there are alternating and mutually exclusive state of stochastic immunoglobulin gene
recombination and cell proliferation with selection. Following successful rearrangement of the Ig heavy chain
gene, Igµ pairs with surrogate light chain (SLC) to form the pre-BCR, expression of which is associated with
clonal large pre-B cell expansion. However, at the subsequent developmental stage, small pre-B cells must fully
exit cell cycle before initiating Ig light chain (IgL) gene recombination. Failure to do so risks genomic instability
and leukemic transformation. Work from our lab and others has demonstrated that the IL-7R drives proliferation
while the pre-BCR primarily appears tasked with IgL recombination. However, there is an apparent paradox in
that IgL rearrangement occurs in small pre-B cells in which there is concurrent strong repression of SLC. There
are two possibilities. The pre-BCR could initiate a complex developmental program in large pre-B cells that is
executed in small pre-B cells. Alternatively, there could be other receptors or mechanisms that orchestrate IgL
chain recombination. We now demonstrate that CXCR4, which is upregulated in small pre-B cells, directly
transmits signals that open Igk to recombination. Indeed, it is CXCR4-mediated ERK activation, and not escape
from IL-7, nor expression of the pre-BCR, that mediates late B lymphopoiesis. These and other data suggest a
new model of B lymphopoiesis in which sequential signaling through three receptors, the IL-7R, pre-BCR and
CXCR4, orchestrate critical cell fate decisions. We propose to test this mode in the following Specific Aims:
Aim 1. Identify the signaling pathways specifically downstream of the pre-BCR.
Aim 2: Determine how CXCR4 signals integrate with pre-BCR/IL-7Resc to drive Igk recombination.
Aim 3. Determine how CXCR4 regulates receptor editing.

## Key facts

- **NIH application ID:** 10117864
- **Project number:** 1R01AI150860-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Marcus Ramsay Clark
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $579,598
- **Award type:** 1
- **Project period:** 2021-03-08 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117864

## Citation

> US National Institutes of Health, RePORTER application 10117864, Role of CXCR4 in immunoglobulin light chain recombination (1R01AI150860-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10117864. Licensed CC0.

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