# Regulation of Normal and Pathogenic B Cell Proliferation by a c-Myc-initiated Transcription Factor Cascade

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $478,281

## Abstract

Summary
Clonal expansion of lymphocytes during the development and immune responses is a hallmark feature of
adaptive immunity. The transcription factor c-MYC is essential to establish metabolically activate states in
activated lymphocytes and allow them to proceed into rapid division cycles. The c-MYC driven clonal
expansion is beneficial for host protection by quantitatively amplifying functional lymphocyte populations. B
lymphocytes also qualitatively improve antibody responses through MYC-dependent proliferative bursts in the
Germinal centers. While c-MYC is thus very important for protective immunity, its aberrant expression has also
been associated with many cancers in humans and mice. Indeed, MYC-expressing proliferating B cells in GCs
and their precursors in the bone marrow are the major sources of B cell malignancies in humans, which might
be worsened by the concurrent presence of genomic insults secondary to activities of RAG proteins and AID
that not only target antigen receptor loci but also a number of cryptic targets. Then, how GC B cells or B cell
precursors minimize the risk of deleterious outcomes while facing the need for MYC-driven clonal expansion?
We have recently found that proliferating lymphocytes temporally restrict c-MYC expression during their clonal
expansion. In the GCs, B cells use c-MYC only for the initiation of proliferative program and utilize its
downstream factor AP4 to continue their divisions. This c-MYC-AP4 transcription factor hand-off is required for
the requisite GC responses for the development of protective antibodies against chronic viral infection. Since
this cascade allows GC B cells to spatially and temporally segregate c-MYC expression in the light zone and
AID activity in the dark zone, this mechanism may indirectly or passively contribute to protection of GC B cells
if AP4 is less oncogenic compared to c-MYC. Unexpectedly, we have obtained preliminary results indicating
that AP4 functions as a tumor suppressor MYC-driven B cell leukemia in a completely independent set of
experiments. These results suggest that the MYC-AP4 axis is essential to support requisite B cell proliferation
for protective immunity and simultaneously protect proliferating B cells from oncogenic transformation. This
may highlight a novel, counterintuitive function of a MYC-induced gene regulatory pathway that functions as a
tumor suppressor. In this grant, we will study the mechanisms of MYC-independent maintenance of AP4 by T
cell help signals, which is necessary for durable proliferation of normal B cells and those of AP4-mediated
tumor suppression.

## Key facts

- **NIH application ID:** 9990687
- **Project number:** 5R01AI130152-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Takeshi Egawa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $478,281
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990687

## Citation

> US National Institutes of Health, RePORTER application 9990687, Regulation of Normal and Pathogenic B Cell Proliferation by a c-Myc-initiated Transcription Factor Cascade (5R01AI130152-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9990687. Licensed CC0.

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