# Synergy of NF-kB and Notch signaling in B cell lymphomatous transformation and B cell plasticity

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2020 · —

## Abstract

NF-kB and Notch signaling are activated in almost all common B cell lymphomas due to either activating
somatic mutations or upregulation of pathway regulators. However, how these two pathways synergistically
regulate B cell development and lymphomatous transformation are unclear. B cell plasticity has been
recognized clinically decades ago. Patient with B cell lymphoma occasionally develop clonally-related myeloid
tumors, suggesting that at least some myeloid tumors develop from malignant or premalignant B cells.
Clinically, these patients typically present with advanced disease with a poor prognosis due to diagnostic
difficulties and lack of standard treatment. The question is, how do B cells convert to myeloid lineage?
Experimentally, forced expression of myeloid transcription factor, CEBPa, in mature B cells induces B-myeloid
conversion. However, whether CEBPa initiates B-myeloid conversion in pathological conditions and whether
other signaling pathways are also involved are largely unknown. Our preliminary data show that concurrent
activation of both pathways in CD19+ B cells efficiently induces B cell lymphomatous transformation in sharp
contrast to activation of either pathway alone. Intriguingly and unexpectedly, transplanted doubly-activated
marginal zone precursor B cells, but not marginal zone B cells, converted to myeloid cells through
dedifferentiation, and some transformed to myeloid leukemia with clonal immunoglobulin VDJ recombination.
Our central hypothesis is that concurrent activation of NF-kB and Notch signaling accelerates B cell
transformation and triggers B-myeloid conversion mainly through downregulation of Bach2 and upregulation of
Ezh2. We will test this hypothesis with the following two independent specific aims: 1) To determine the
mechanism whereby concurrent activation of NF-kB/Notch signaling induces B cell transformation, and 2) To
determine the mechanism whereby concurrent activation of NF-kB/Notch signaling induces B-myeloid
conversion and transformation. The expected results are highly relevant to understanding the synergistic role
of NF-kB/Notch signaling in B cell plasticity and malignant transformation. Importantly, our results suggest that
adding Notch, NF-kB and/or Ezh2 inhibitors to the current lymphoma therapeutic regimens could not only
improve lymphoma treatment, but also prevent myeloid neoplasm conversion.

## Key facts

- **NIH application ID:** 9841720
- **Project number:** 5I01BX004255-02
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Chen Zhao
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841720

## Citation

> US National Institutes of Health, RePORTER application 9841720, Synergy of NF-kB and Notch signaling in B cell lymphomatous transformation and B cell plasticity (5I01BX004255-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841720. Licensed CC0.

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